Muscarinic acetylcholine receptor antagonists

ABSTRACT

Muscarinic Acetylcholine Receptor Antagonists and methods of using them are provided.

This application is a continuation application of U.S. Ser. No.11/568,330, filed 3 May 2007, which is the §371 national stage entry ofPCT/US2005/014386, filed 27 Apr. 2005 and which claims the benefit ofpriority from U.S. Ser. No. 60/565,623, filed 27 Apr. 2004.

FIELD OF THE INVENTION

This invention relates to novel quinuclidines derivatives,pharmaceutical compositions, and use thereof in treating muscarinicacetylcholine receptor mediated diseases of the respiratory tract.

BACKGROUND OF THE INVENTION

Acetylcholine released from cholinergic neurons in the peripheral andcentral nervous systems affects many different biological processesthrough interaction with two major classes of acetylcholinereceptors—the nicotinic and the muscarinic acetylcholine receptors.Muscarinic acetylcholine receptors (mAChRs) belong to the superfamily ofG-protein coupled receptors that have seven transmembrane domains. Thereare five subtypes of mAChRs, termed M₁-M₅, and each is the product of adistinct gene. Each of these five subtypes displays uniquepharmacological properties. Muscarinic acetylcholine receptors arewidely distributed in vertebrate organs where they mediate many of thevital functions. Muscarinic receptors can mediate both inhibitory andexcitatory actions. For example, in smooth muscle found in the airways,M₃ mAChRs mediate contractile responses. For review, please seeCaulfield (1993 Pharmac. Ther. 58:319-79).

In the lungs, mAChRs have been localized to smooth muscle in the tracheaand bronchi, the submucosal glands, and the parasympathetic ganglia.Muscarinic receptor density is greatest in parasympathetic ganglia andthen decreases in density from the submucosal glands to tracheal andthen bronchial smooth muscle. Muscarinic receptors are nearly absentfrom the alveoli. For review of mAChR expression and function in thelungs, please see Fryer and Jacoby (1998 Am J Respir Crit Care Med158(5, pt 3) S 154-60).

Three subtypes of mAChRs have been identified as important in the lungs,M₁, M₂ and M₃ mAChRs. The M₃ mAChRs, located on airway smooth muscle,mediate muscle contraction. Stimulation of M₃ mAChRs activates theenzyme phospholipase C via binding of the stimulatory G protein Gq/11(Gs), leading to liberation of phosphatidyl inositol-4,5-bisphosphate,resulting in phosphorylation of contractile proteins. M₃ mAChRs are alsofound on pulmonary submucosal glands. Stimulation of this population ofM₃ mAChRs results in mucus secretion.

M₂ mAChRs make up approximately 50-80% of the cholinergic receptorpopulation on airway smooth muscles. Although the precise function isstill unknown, they inhibit catecholaminergic relaxation of airwaysmooth muscle via inhibition of cAMP generation. Neuronal M₂ mAChRs arelocated on postganglionic parasympathetic nerves. Under normalphysiologic conditions, neuronal M₂ mAChRs provide tight control ofacetylcholine release from parasympathetic nerves. Inhibitory M₂ mAChRshave also been demonstrated on sympathetic nerves in the lungs of somespecies. These receptors inhibit release of noradrenaline, thusdecreasing sympathetic input to the lungs.

M₁ mAChRs are found in the pulmonary parasympathetic ganglia where theyfunction to enhance neurotransmission. These receptors have also beenlocalized to the peripheral lung parenchyma, however their function inthe parenchyma is unknown.

Muscarinic acetylcholine receptor dysfunction in the lungs has beennoted in a variety of different pathophysiological states. Inparticular, in asthma and chronic obstructive pulmonary disease (COPD),inflammatory conditions lead to loss of inhibitory M₂ muscarinicacetylcholine autoreceptor function on parasympathetic nerves supplyingthe pulmonary smooth muscle, causing increased acetylcholine releasefollowing vagal nerve stimulation (Fryer et al. 1999 Life Sci 64 (6-7)449-55). This mAChR dysfunction results in airway hyperreactivity andhyperresponsiveness mediated by increased stimulation of M₃ mAChRs. Thusthe identification of potent mAChR antagonists would be useful astherapeutics in these mAChR-mediated disease states.

COPD is an imprecise term that encompasses a variety of progressivehealth problems including chronic bronchitis, chronic bronchiolitis andemphysema, and it is a major cause of mortality and morbidity in theworld. Smoking is the major risk factor for the development of COPD;nearly 50 million people in the U.S. alone smoke cigarettes, and anestimated 3,000 people take up the habit daily. As a result, COPD isexpected to rank among the top five as a world-wide health burden by theyear 2020. Inhaled anti-cholinergic therapy is currently considered the“gold standard” as first line therapy for COPD (Pauwels et al. 2001 Am.J. Respir. Crit. Care Med. 163:1256-1276).

Despite the large body of evidence supporting the use ofanti-cholinergic therapy for the treatment of airway hyperreactivediseases, relatively few anti-cholinergic compounds are available foruse in the clinic for pulmonary indications. More specifically, inUnited States, Ipratropium Bromide (Atrovent©; and Combivent©, incombination with albuterol) is currently the only inhaledanti-cholinergic marketed for the treatment of airway hyperreactivediseases. While this compound is a potent anti-muscarinic agent, it isshort acting, and thus must be administered as many as four times dailyin order to provide relief for the COPD patient. In Europe and Asia, thelong-acting anti-cholinergic Tiotropium Bromide (Spiriva©) was recentlyapproved, however this product is currently not available in the UnitedStates. Thus, there remains a need for novel compounds that are capableof causing blockade at mAChRs which are long acting and can beadministered once-daily for the treatment of airway hyperreactivediseases such as asthma and COPD.

Since mAChRs are widely distributed throughout the body, the ability toapply anti-cholinergics locally and/or topically to the respiratorytract is particularly advantageous, as it would allow for lower doses ofthe drug to be utilized. Furthermore, the ability to design topicallyactive drugs that have long duration of action, and in particular, areretained either at the receptor or by the lung, would allow theavoidance of unwanted side effects that may be seen with systemicanti-cholinergic use.

SUMMARY OF THE INVENTION

This invention provides for a method of treating a muscarinicacetylcholine receptor (mAChR) mediated disease, wherein acetylcholinebinds to an mAChR and which method comprises administering an effectiveamount of a compound of Formula (I) or a pharmaceutically acceptablesalt thereof.

This invention also relates to a method of inhibiting the binding ofacetylcholine to its receptors in a mammal in need thereof whichcomprises administering to aforementioned mammal an effective amount ofa compound of Formula (I).

The present invention also provides for the novel compounds of Formula(I), and pharmaceutical compositions comprising a compound of Formula(I), and a pharmaceutical carrier or diluent.

Compounds of Formula (I) useful in the present invention are representedby the structure:

wherein:

-   R1 is selected from the group consisting of C1-15 alkyl,    halosubstituted C1-15 alkyl, C1-15 alkyl cycloalkyl, cycloalkyl,    C2-15 alkenyl, hydroxy substituted C1-15 alkyl, C1-15 alkyl aryl,    C1-15 alkyl heteroaryl, (CR7R7)qNRaRa, (CR7R7)qNC(O)Ra,    (CR7R7)qC(O)NRaRa, (CR7R7)qC(O)Ra, (CR7R7)qOC(O)Ra,    (CR7R7)qNRaC(O)NRaRa, (CR7R7)qORc and (CR7R7)qNS(O)₂Ra-   R1 is selected from the group consisting of:

-   R1 is selected from the group consisting of:

-   R2 and R3 are independently selected from the group consisting of    aryl, C1-4 alkyl aryl, heteroaryl, C1-4 alkyl heteroaryl,    heterocyclic and a C1-4 alkyl heterocyclic moiety, all of which    moieties may be optionally substituted;-   Ra is selected from the group consisting of hydrogen, C1-15 alkyl,    C1-15 alkoxy, aryl, C1-15 alkyl aryl, heteroaryl, C1-15 alkyl    heteroaryl, heterocyclic and a C1-15 alkyl heterocyclic moiety, all    of which moieties may be optionally substituted;-   Rc is selected from the group consisting of hydrogen, C1-15 alkyl,    C1-15 alkoxy, heterocyclic and a C1-15 alkyl heterocyclic moiety,    all of which moieties may be optionally substituted;-   R4 and R5 are independently selected from the group consisting of    hydrogen, halogen, C1-4 alkyl, aryl, C1-4 alkyl aryl, cyano, nitro,    (CR7R7)pORb, (CR7R7)pNRbRb, or R4 and R5 together may form a 5 to 6    membered saturated or unsaturated ring; and wherein the alkyl, aryl,    arylalkyl, heteroaryl, heteroalkyl, heterocyclic, heterocyclicalkyl    groups may be optionally substituted;-   R6 is selected from the group consisting of hydrogen, C1-4 alkyl;-   q is 0 or an integer having a value of 1 to 15;-   n is an integer having a value of 1 to 14;-   m is an integer having a value of 1 to 15;-   1 is an integer having a value of 1 to 4;-   t is 0 or an integer having a value of 1 to 5;-   p is 0 or an integer having a value of 1 to 4;-   X, Y, Z and W are independently selected from the group consisting    of hydrogen, C1-4 alkyl;-   V is selected from the group consisting of CH₂, O, S, and NRb;-   M is O or CH₂;-   Rb is selected from the group consisting of hydrogen, C1-4 alkyl,    aryl and C1-4 alkyl aryl;-   R7 is selected from the group consisting of hydrogen, C1-4 alkyl,    halosubstituted C1-4 alkyl, and hydroxysubstituted C1-4 alkyl;-   X— is a physiologically acceptable anion, such as chloride, bromide,    iodide, hydroxide, sulfate, nitrate, phosphate, acetate,    trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate,    mandelate, methanesulfonate and p-toluenesulfonate.

DETAILED DESCRIPTION OF THE INVENTION

This invention related to novel bi-aryl 8-azoniabicyclo[3.2.1]octanecompounds, pharmaceutical compositions, processes for their preparation,and use thereof in treating mAChR mediated diseases.

In a preferred embodiment of the present invention the compound is offormula (I) herein below:

wherein:

-   R1 is selected from the group consisting of C1-10 alkyl,    halosubstituted C1-10 alkyl, C1-10 alkyl aryl, C1-10 alkyl    cycloalkyl, cycloalkyl, hydroxy substituted C1-10 alkyl, C2-10    alkenyl, (CR7R7)qORc; (CR7R7)qOC(O)Ra and (CR7R7)qNS(O)₂Ra;-   or R1 is selected from the group consisting of:

-   R2 and R3 are, independently, selected from the group consisting of:

-   F, G, H, K and L are independently selected from the group    consisting of hydrogen, halogen, C1-4 alkyl, halosubstituted C1-4    alkyl, hydroxysubstituted C1-4 alkyl, and C1-4 alkoxy;-   Ra is selected from the group consisting of hydrogen, C1-10 alkyl,    C1-10 alkoxy, aryl and heteroaryl, all of which moieties may be    optionally substituted;-   Rc is selected from the group consisting of hydrogen, C1-5 alkyl,    C1-5 alkoxy, all of which moieties may be optionally substituted;-   R4 and R5 are independently selected from the group consisting of    hydrogen, halogen, C1-4 alkyl, aryl, C1-4 alkyl aryl, cyano, nitro,    (CR7R7)pORb, (CR7R7)pNRbRb, or R4 and R5 together may form a 5 to 6    membered saturated or unsaturated ring;-   q is 0 or an integer having a value of 1 to 5;-   n is an integer having a value of 1 to 4;-   m is an integer having a value of 1 to 5;-   l is 1 or 2;-   t is 0, 1 or 2;-   p is 0, 1 or 2;-   V is O, or CH₂;-   R6 is selected from the group consisting of hydrogen, C1-4 alkyl;-   M is O or CH₂;-   Rb is selected from the group consisting of hydrogen, C1-4 alkyl,    and aryl C1-4 alkyl R7 is selected from the group consisting of    hydrogen, and C1-4 alkyl;-   X— is a physiologically acceptable anion, such as chloride, bromide,    iodide, hydroxide, sulfate, nitrate, phosphate, acetate,    trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate,    mandelate, methanesulfonate and p-toluenesulfonate.

All of the aryl, heteroaryl, and heterocyclic containing moieties may beoptionally substituted as defined herein below.

For use herein the term “the aryl, heteroaryl, and heterocycliccontaining moieties” refers to both the ring and the alkyl, or ifincluded, the alkenyl rings, such as aryl, arylalkyl, and aryl alkenylrings. The term “moieties” and “rings” may be interchangeably usedthroughout.

As used herein, “optionally substituted” unless specifically definedshall mean such groups as halogen, such as fluorine, chlorine, bromineor iodine; hydroxy; hydroxy substituted C₁₋₁₀alkyl; C₁₋₁₀ alkoxy, suchas methoxy or ethoxy; S(O)_(m′)C₁₋₁₀ alkyl, wherein m′ is 0, 1 or 2,such as methyl thio, methyl sulfinyl or methyl sulfonyl; amino, mono &di-substituted amino, such as in the NR₁₀R₁₁ group; NHC(O)R₉;C(O)NR₁₀R₁₁; C(O)OH; S(O)₂NR₁₀R₁₁; NHS(O)₂R₉, C₁₋₁₀ alkyl, such asmethyl, ethyl, propyl, isopropyl, or t-butyl; halosubstituted C₁₋₁₀alkyl, such CF₃; an optionally substituted aryl, such as phenyl, or anoptionally substituted arylalkyl, such as benzyl or phenethyl,optionally substituted heterocylic, optionally substitutedheterocyclicalkyl, optionally substituted heteroaryl, optionallysubstituted heteroaryl alkyl, wherein these aryl, heteroaryl, orheterocyclic moieties may be substituted one to two times by halogen;hydroxy; hydroxy substituted alkyl; C₁₋₁₀ alkoxy; S(O)_(m)′C₁₋₁₀ alkyl;amino, mono & di-substituted alkyl amino, such as in the NR₁₀R₁₁ group;C₁₋₁₀ alkyl, or halosubstituted C₁₋₁₀ alkyl, such as CF₃.

The following terms, as used herein, refer to:

-   -   “halo”—all halogens, that is chloro, fluoro, bromo and iodo.    -   “C₁₋₁₀alkyl” or “alkyl”—both straight and branched chain        moieties of 1 to 10 carbon atoms, unless the chain length is        otherwise limited, including, but not limited to, methyl, ethyl,        n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,        n-pentyl and the like.    -   “cycloalkyl” is used herein to mean cyclic moiety, preferably of        3 to 8 carbons, including but not limited to cyclopropyl,        cyclopentyl, cyclohexyl, and the like.    -   “alkenyl” is used herein at all occurrences to mean straight or        branched chain moiety of 2-10 carbon atoms, unless the chain        length is limited thereto, including, but not limited to        ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl,        2-butenyl and the like.    -   “aryl”—phenyl and naphthyl;    -   “heteroaryl” (on its own or in any combination, such as        “heteroaryloxy”, or “heteroaryl alkyl”)—a 5-10 membered aromatic        ring system in which one or more rings contain one or more        heteroatoms selected from the group consisting of N, O or S,        such as, but not limited, to pyrrole, pyrazole, furan,        thiophene, quinoline, isoquinoline, quinazolinyl, pyridine,        pyrimidine, oxazole, tetrazole, thiazole, thiadiazole, triazole,        imidazole, indole or benzimidazole.    -   “heterocyclic” (on its own or in any combination, such as        “heterocyclicalkyl”)—a saturated or partially unsaturated 4-10        membered ring system in which one or more rings contain one or        more heteroatoms selected from the group consisting of N, O, or        S; such as, but not limited to, pyrrolidine, piperidine,        piperazine, morpholine, tetrahydropyran, thiomorpholine, or        imidazolidine. Furthermore, sulfur may be optionally oxidized to        the sulfone or the sulfoxide.    -   “arylalkyl” or “heteroarylalkyl” or “heterocyclicalkyl” is used        herein to mean C₁₋₁₀ alkyl, as defined above, attached to an        aryl, heteroaryl or heterocyclic moiety, as also defined herein,        unless otherwise indicated.    -   “sulfinyl”—the oxide S(O) of the corresponding sulfide, the term        “thio” refers to the sulfide, and the term “sulfonyl” refers to        the fully oxidized S(O)₂ moiety.    -   “wherein two R₁ moieties (or two Y moieties) may together form a        5 or 6 membered saturated or unsaturated ring” is used herein to        mean the formation of an aromatic ring system, such as        naphthalene, or is a phenyl moiety having attached a 6 membered        partially saturated or unsaturated ring such as a C₆        cycloalkenyl, i.e. hexene, or a C₅ cycloalkenyl moiety, such as        cyclopentene.        Illustrative compounds of Formula (I) include:

-   1-(2-{[(3-fluorophenyl)methyl]oxy}ethyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   1-(2-{[(4-bromophenyl)methyl]oxy}ethyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   1-(2-{[(4-chlorophenyl)methyl]oxy}ethyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[bis(4-fluorophenyl)(hydroxy)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   4-{hydroxy[bis(3-methylphenyl)]methyl}-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   1-(2-{[(4-fluorophenyl)methyl]oxy}ethyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylcarbonyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   1-{3-[(3-fluorophenyl)oxy]propyl}-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-{hydroxy[bis(4-methylphenyl)]methyl}-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-{3-[(methylsulfonyl)amino]propyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[bis(3-fluorophenyl)(hydroxy)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   1-{3-[(3-chlorophenyl)oxy]propyl}-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(di-2-thienyl)methyl]-1-[3-(phenyloxy)propyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-[3-(phenyloxy)propyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   1-(2-{[(4-cyanophenyl)methyl]oxy}ethyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   1-{3-[(4-bromophenyl)oxy]propyl}-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[bis(4-fluorophenyl)(hydroxy)methyl]-1-[3-(phenyloxy)propyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   1-{3-[(4-fluorophenyl)oxy]propyl}-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-{2-[(1-methyl-1-phenylethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-{2-[(2-naphthalenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(di-3-thienyl)methyl]-1-[3-(phenyloxy)propyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-[2-(phenyloxy)ethyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-{hydroxy[bis(3-methylphenyl)]methyl}-1-[3-(phenyloxy)propyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-{hydroxy[bis(4-methylphenyl)]methyl}-1-[3-(phenyloxy)propyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-(3-{[4-(methyloxy)phenyl]oxy}propyl)-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-[3-(2-naphthalenyloxy)propyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-[2-({[3-(methyloxy)phenyl]methyl}oxy)ethyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-(2-naphthalenylmethyl)-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[bis(3-fluorophenyl)(hydroxy)methyl]-1-[3-(phenyloxy)propyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(di-2-thienyl)methyl]-1-[2-(phenyloxy)ethyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-(hydroxy{bis[3-(methyloxy)phenyl]}methyl)-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-{3-[(4-nitrophenyl)oxy]propyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   1-{3-[(2-fluorophenyl)oxy]propyl}-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-{3-[(3-nitrophenyl)oxy]propyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-({3-[(trifluoromethyl)oxy]phenyl}methyl)-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-[(5-nitro-2-furanyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-[2-(1H-indol-3-yl)ethyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   1-[3-(4-biphenylyloxy)propyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-{3-[(2-methylphenyl)oxy]propyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-(phenylmethyl)-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-(2-{[2-(methyloxy)ethyl]oxy}ethyl)-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-{3-[(phenylmethyl)oxy]propyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-[4-(phenyloxy)butyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   1-(1,3-dioxolan-2-ylmethyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-{3-[(2-hydroxyphenyl)oxy]propyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   1-hexyl-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(di-3-thienyl)methyl]-1-[2-(phenyloxy)ethyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-[3-({4-[(phenylmethyl)oxy]phenyl}oxy)propyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   1-[(3-bromophenyl)methyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(di-2-naphthalenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-[2-(methyloxy)ethyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-(hydroxy{bis[4-(methyloxy)phenyl]}methyl)-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   1-{3-[(4-cyanophenyl)oxy]propyl}-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   1-[2-(1-benzofuran-2-yl)-2-oxoethyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   1-[2-({[4-(1,1-dimethylethyl)phenyl]methyl}oxy)ethyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-{[3-(methyloxy)phenyl]methyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-({4-[(trifluoromethyl)oxy]phenyl}methyl)-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-nonyl-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(di-2-naphthalenyl)methyl]-1-[3-(phenyloxy)propyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   1-[(4-fluorophenyl)methyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   1-[(4-bromophenyl)methyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-{[3-(trifluoromethyl)phenyl]methyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   1-[(2-fluorophenyl)methyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-{[4-(trifluoromethyl)phenyl]methyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   1-(5-hexen-1-yl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   1-(3-cyclohexylpropyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-(2-phenylethyl)-1-azoniabicyclo[2.2.2]octane    bromide

-   1-ethyl-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-[(4-methylphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   1-butyl-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-[2-(3-methyl-1H-pyrazol-1-yl)ethyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-(hydroxy{bis[4-(methyloxy)phenyl]}methyl)-1-[3-(phenyloxy)propyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   1-[3-(3-biphenylyloxy)propyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-[(1S)-1-methyl-2-oxo-2-(phenylamino)ethyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-propyl-1-azoniabicyclo[2.2.2]octane    bromide

-   1-{3-[(2-bromophenyl)oxy]propyl}-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   1-[(3-fluorophenyl)methyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   1-[(3,4-dichlorophenyl)methyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   1-[(2-fluoro-3-methylphenyl)methyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-{4-[(phenylmethyl)oxy]butyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   1-[(4-cyanophenyl)methyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-(hydroxy{bis[3-(methyloxy)phenyl]}methyl)-1-[3-(phenyloxy)propyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   1-(3-{[3-(diethylamino)phenyl]oxy}propyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-(2-propen-1-yl)-1-azoniabicyclo[2.2.2]octane    bromide

-   1-{[4-(1,1-dimethylethyl)phenyl]methyl}-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane    bromide

-   1-[(2,6-difluorophenyl)methyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-[2-({[2-(phenyloxy)-3-pyridinyl]carbonyl}amino)ethyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(di-2-thienyl)methyl]-1-(2-phenylethyl)-1-azoniabicyclo[2.2.2]octane    bromide

-   1-(3-bromopropyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-(2-hydroxyethyl)-1-azoniabicyclo[2.2.2]octane    bromide

-   1-[(3-cyanophenyl)methyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   1-[2-({[(2,4-dichlorophenyl)amino]carbonyl}amino)ethyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-(4-penten-1-yl)-1-azoniabicyclo[2.2.2]octane    bromide

-   1-{2-[(2,4-dibromophenyl)oxy]ethyl}-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   1-[(2,4-difluorophenyl)methyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-[3-(methyloxy)propyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-[3-({2-[(phenylmethyl)oxy]phenyl}oxy)propyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   1-[(2-aminoethyl)-1-azoniabicyclo[2.2.2]oct-4-yl]    (diphenyl)methanolate trifluoroacetate

-   4-[hydroxy(di-2-thienyl)methyl]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-methyl-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-(tetrahydro-2H-pyran-2-ylmethyl)-1-azoniabicyclo[2.2.2]octane    bromide

-   1-[(2,3-difluorophenyl)methyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   1-[2-(4-biphenylyl)-2-oxoethyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-[2-oxo-2-(4-pentylphenyl)ethyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   1-(2-{[(2,4-dichlorophenyl)carbonyl]amino}ethyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-(3-{[2-(methyloxy)phenyl]oxy}propyl)-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-[(1-{[(phenylmethyl)oxy]carbonyl}-4-piperidinyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-[2-(2-naphthalenyl)-2-oxoethyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-[(4-nitrophenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   1-butyl-4-[hydroxy(di-3-thienyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane    bromide

-   1-[(3,4-difluorophenyl)methyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   1-(cyclopropylmethyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide    The preferred compounds useful in the present invention include:

-   1-(2-{[(3-fluorophenyl)methyl]oxy}ethyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   1-(2-{[(4-bromophenyl)methyl]oxy}ethyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   1-(2-{[(4-chlorophenyl)methyl]oxy}ethyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[bis(4-fluorophenyl)(hydroxy)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   4-{hydroxy[bis(3-methylphenyl)]methyl}-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   1-(2-{[(4-fluorophenyl)methyl]oxy}ethyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylcarbonyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   1-{3-[(3-fluorophenyl)oxy]propyl}-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-{hydroxy[bis(4-methylphenyl)]methyl}-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-{3-[(methylsulfonyl)amino]propyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[bis(3-fluorophenyl)(hydroxy)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   1-{3-[(3-chlorophenyl)oxy]propyl}-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(di-2-thienyl)methyl]-1-[3-(phenyloxy)propyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-[3-(phenyloxy)propyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   1-(2-{[(4-cyanophenyl)methyl]oxy}ethyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   1-{3-[(4-bromophenyl)oxy]propyl}-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[bis(4-fluorophenyl)(hydroxy)methyl]-1-[3-(phenyloxy)propyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   1-{3-[(4-fluorophenyl)oxy]propyl}-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-{2-[(1-methyl-1-phenylethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-{2-[(2-naphthalenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(di-3-thienyl)methyl]-1-[3-(phenyloxy)propyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-[2-(phenyloxy)ethyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-{hydroxy[bis(3-methylphenyl)]methyl}-1-[3-(phenyloxy)propyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-{hydroxy[bis(4-methylphenyl)]methyl}-1-[3-(phenyloxy)propyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-(3-{[4-(methyloxy)phenyl]oxy}propyl)-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-[3-(2-naphthalenyloxy)propyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-[2-({[3-(methyloxy)phenyl]methyl}oxy)ethyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-(2-naphthalenylmethyl)-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[bis(3-fluorophenyl)(hydroxy)methyl]-1-[3-(phenyloxy)propyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(di-2-thienyl)methyl]-1-[2-(phenyloxy)ethyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-(hydroxy{bis[3-(methyloxy)phenyl]}methyl)-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-{3-[(4-nitrophenyl)oxy]propyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   1-{3-[(2-fluorophenyl)oxy]propyl}-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide    The more preferred compounds useful in the present invention    include:

-   1-(2-{[(3-fluorophenyl)methyl]oxy}ethyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   1-(2-{[(4-bromophenyl)methyl]oxy}ethyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   1-(2-{[(4-chlorophenyl)methyl]oxy}ethyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[bis(4-fluorophenyl)(hydroxy)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   4-{hydroxy[bis(3-methylphenyl)]methyl}-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   1-(2-{[(4-fluorophenyl)methyl]oxy}ethyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylcarbonyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   1-{3-[(3-fluorophenyl)oxy]propyl}-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-{hydroxy[bis(4-methylphenyl)]methyl}-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-{3-[(methylsulfonyl)amino]propyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[bis(3-fluorophenyl)(hydroxy)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   1-{3-[(3-chlorophenyl)oxy]propyl}-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(di-2-thienyl)methyl]-1-[3-(phenyloxy)propyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-[3-(phenyloxy)propyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   1-(2-{[(4-cyanophenyl)methyl]oxy}ethyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   1-{3-[(4-bromophenyl)oxy]propyl}-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[bis(4-fluorophenyl)(hydroxy)methyl]-1-[3-(phenyloxy)propyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   1-{3-[(4-fluorophenyl)oxy]propyl}-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-{2-[(1-methyl-1-phenylethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-{2-[(2-naphthalenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(di-3-thienyl)methyl]-1-[3-(phenyloxy)propyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-[2-(phenyloxy)ethyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-{hydroxy[bis(3-methylphenyl)]methyl}-1-[3-(phenyloxy)propyl]-1-azoniabicyclo[2.2.2]octane    bromide    The most preferred compounds useful in the present invention    include:

-   1-(2-{[(3-fluorophenyl)methyl]oxy}ethyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   1-(2-{[(4-bromophenyl)methyl]oxy}ethyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   1-(2-{[(4-chlorophenyl)methyl]oxy}ethyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[bis(4-fluorophenyl)(hydroxy)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   4-{hydroxy[bis(3-methylphenyl)]methyl}-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane    bromide

-   1-(2-{[(4-fluorophenyl)methyl]oxy}ethyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane    bromide

-   4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylcarbonyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane    bromide

Methods of Preparation

The compounds of Formula (I) may be obtained by applying syntheticprocedures, some of which are illustrated in the Schemes below. Thesynthesis provided in this Scheme is applicable for producing compoundsof Formula (I) having a variety of different R1, R2 and R3 groups whichare reacted, employing substituents which are suitably protected, toachieve compatibility with the reactions outlined herein. Subsequentdeprotection, in those cases, then affords compounds of the naturegenerally disclosed. While the Schemes are shown with compounds only ofFormula (I), this is merely for illustration purpose only.

As shown in Scheme 1, the desired compounds of Formula (I) can beprepared in four synthetic steps from the commercially available ethyl4-piperidinecarboxylate precursor 1. Compound 1 is reacted with1-bromo-2-chloroethane following standard alkylation procedures wellknown in the art such as potassium carbonate in acetone followed byreaction of the intermediate with lithium diisopropylamide in an aproticsolvent such as tetrahydrofurann to give the quinuclidine intermediate2. Condensation of compound 2 with organometallic reagents such as aGrignard reagent or an organolithium derivative in an aprotic solventsuch as tetrahydrofuran, results in the formation of the tertiaryalcohol 3 of Formula (I) (R1=nothing). Further N-alkylation of compound3 with a suitable alkyl halide in a organic solvent such as chloroformor acetonitrile gives compound 4 of Formula (I) (R1 not nothing).

Reagents and conditions: a) 1-bromo-2-chloroethane, K₂CO₃, acetone; b)LDA, THF; c) R₂M then R₃M, THF; d) R1X, ACN, CHCl₃.

SYNTHETIC EXAMPLES

The invention will now be described by reference to the followingExamples which are merely illustrative and are not to be construed as alimitation of the scope of the present invention. All temperatures aregiven in ° C. Thin layer chromatography (t.l.c.) was carried out onsilica and column chromatography on silica (Flash column chromatographyusing Merck 9385 unless stated otherwise). The following are theexperimental conditions for the LC-MS.

LC-MS Experimental Conditions:

Liquid Chromatograph: System: Shimadzu LC system with SCL-10A Controllerand dual UV detector Autosampler: Leap CTC with a Valco six portinjector Column: Aquasil/Aquasil (C18 40 × 1 mm) Inj. Volume (μL): 2.0Solvent A: H₂O, 0.02% TFA Solvent B: MeCN, 0.018% TFA Gradient: linearChannel A: UV 214 nm Channel B: ELS Step Time (min) Dura. (min) Flow(μL/min) Sol. A Sol. B 0 0.00 0.00 300.00 95.00 5.00 1 0.00 0.01 300.0095.00 5.00 2 0.01 3.20 300.00 10.00 90.00 3 3.21 1.00 300.00 10.00 90.004 4.21 0.10 300.00 95.00 5.00 5 4.31 0.40 300.00 95.00 5.00 MassSpectrometer: PE Sciex Single Quadrupole LC/MS API-150 Polarity:Positive Acquisition mode: ProfileThe preparatory HPLC was conducted using a Gilson HPLC system under thefollowing conditions:

-   -   Column: 75×33 mm I. D., S-5 um, 12 nm    -   Flow rate: 30 mL/min    -   Injection Volume: 0.800 mL    -   Room temperature    -   Solvent A: water    -   Solvent B: acetonitrile

All solvents used herein are of the highest available purity and allreactions are run under anhydrous conditions under an air atmosphereunless otherwise indicated.

Example 1 Preparation of 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanolEthyl 1-(2-chloroethyl)-4-piperidinecarboxylate

To a solution of ethyl nipecotate (20.0 mL, 130 mmol) in acetone (180mL) was added 1-bromo-2-chloroethane (21.6 mL, 260 mmol) followed byanhydrous K₂CO₃ (27.12 g, 196 mmol). The reaction mixture was stirredfor 24 h and then concentrated under vacuum. The resulting residue wastreated with H₂O (75 mL) and extracted with Et₂O. The combined organiclayers were dried with MgSO₄, filtered, and concentrated under vacuum.Purification of the crude residue by flash chromatography (50% Et₂O/50%hexane) on silica gel gave the title compound (10.99 g, 38.6%). EI-MSm/z 220(M+H⁺) Rt (1.20 min).

Ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate

A solution of ethyl 1-(2-chloroethyl)-4-piperidinecarboxylate (20.42 g,92.9 mmol) in THF (600 mL) was cooled to −50° C. under Ar. LDA (2.0 M inheptane/THF/ethyl benzene, 70 mL, 140 mmol) was slowly added to thesolution at −50° C. over 25 min. The reaction was allowed to warm up toroom temperature over 16 h. The reaction was quenched with K₂CO₃(saturated aqueous) (500 mL) and extracted with Et₂O (3×500 mL). Thecombined organic layers were dried over MgSO₄, filtered, andconcentrated under vacuum. The resulting orange oil was co-evaporatedthree times with DCM to remove excess ethyl benzene, resulting in thetitle compound (16.29 g, 95.7%). EI-MS m/z 184(M+H⁺) Rt (1.08 min).

1-Azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol

A solution of phenyllithium (1.5-1.7 M in 70 cyclohexane/30 ether, 20.0mL, 32 mmol) was chilled down to −30° C. under Ar. Ethyl1-azabicyclo[2.2.2]octane-4-carboxylate (1.51 g, 8.23 mmol) in THF (20mL) was slowly added to the reaction mixture at −30° C. over 25 min. Thereaction was allowed to warm up to room temperature over 16 h. Thereaction was quenched with H₂O and then evaporated to dryness undervacuum. H₂O and EtOAc were added, causing a white solid to crash out.This solid was filtered off, to give the title compound (0.79 g). Theaqueous phase was further extracted with EtOAc, the combined organiclayers were dried over MgSO₄, filtered, and concentrated under vacuum.The crude product was treated with EtOAc and hexane and filtered toyield more of the title compound (0.67 g). Total yield (1.46 g, 60.7%).EI-MS m/z 294(M+H⁺) Rt (1.37 min).

Example 2 Preparation of4-[hydroxy(diphenyl)methyl]-1-(2-phenylethyl)-1-azoniabicyclo[2.2.2]octanebromide

To a solution of 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0775g, 0.264 mmol) in CH₃CN/DCM/MeOH (2 mL/2 mL/1 mL) was added(2-bromoethyl)benzene (0.38 mL, 2.78 mmol). The solution was allowed tostir at room temperature for 4 days and then concentrated under vacuumto give a white solid. This residue was dissolved in DMSO and purifiedby preparatory HPLC to give the title compound (0.0612 g, 48.6%). EI-MSm/z 398(M⁺) Rt (2.06 min).

Example 3 Preparation of4-[hydroxy(diphenyl)methyl]-1-[2-(phenyloxy)ethyl]-1-azoniabicyclo[2.2.2]octanebromide

General Procedure for Salt Formation without HPLC Purification.

To a solution of 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.055 0g, 0.187 mmol) in 2 CH₃CN/3 CHCl₃ (2.5 mL) was added 2-bromoethyl phenylether (0.06 0 g, 0.29 mmol). The solution was stirred at 60° C. for 16h. The reaction was cooled down to room temperature and then dilutedwith ethyl acetate and hexane causing a solid to crash out of solution.This solid was filtered off, and washed with hexane to give the titlecompound (0.063 g, 67.6%). EI-MS m/z 414(M⁺) Rt (1.94 min).

Example 4 Preparation of1-(cyclopropylmethyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octanebromide

General Procedure for Salt Formation with HPLC Purification.

To a solution of 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0552g, 0.188 mmol) in 2 CH₃CN/3 CHCl₃ (2.5 mL) was added(bromomethyl)cyclopropane (0.025 mL, 0.257 mmol). The solution washeated at 60° C. for 16 h, cooled down to room temperature and thesolvents evaporated under vacuum. The residue was taken up in 2.5 mL ofDMSO and purified by preparatory HPLC (without TFA) to give the titlecompound (0.031 9 g, 39.9%). EI-MS m/z 348(M⁺) Rt (1.69 min).

Example 5 Preparation of4-[hydroxy(diphenyl)methyl]-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 4,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0567 g, 0.193 mmol) and2-bromo-1-phenylethanone (0.0487 g, 0.245 mmol) in 2 CH₃CN/3 CHCl₃ (2.5mL) were reacted to give the desired product (0.0410 g, 43.0%). EI-MSm/z 412(M⁺) Rt (1.90 min).

Example 6 Preparation of4-[hydroxy(diphenyl)methyl]-1-[3-(phenyloxy)propyl]-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.045 g, 0.153 mmol) and3-bromopropyl phenyl ether (0.035 mL, 0.222 mmol) in 2 CH₃CN/3 CHCl₃(3.0 mL) were reacted to give the desired product (0.0662 g, 86.0%).EI-MS m/z 428(M⁺) Rt (1.97 min).

Example 7 Preparation of4-[hydroxy(diphenyl)methyl]-1-[4-(phenyloxy)butyl]-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 4,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0604 g, 0.206 mmol) and4-bromobutyl phenyl ether (0.106 g, 0.463 mmol) in 2 CH₃CN/3 CHCl₃ (5.0mL) were reacted to give the desired product (0.0649 g, 64.9%). EI-MSm/z 442(M⁺) Rt (2.13 min).

Example 8 Preparation of4-[hydroxy(diphenyl)methyl]-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 4,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0696 g, 0.237 mmol) and2-[(2-bromoethyl)oxy]tetrahydro-2H-pyran (0.080 mL, 0.529 mmol) in 2CH₃CN/3 CHCl₃ (5.0 mL) were reacted to give the desired product (0.0348g, 31.6%). EI-MS m/z 422(M⁺) Rt (1.85 min).

Example 9 Preparation of4-[hydroxy(diphenyl)methyl]-1-{4-[(phenylmethyl)oxy]butyl}-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 4,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0646 g, 0.220 mmol) and4-bromobutyl phenylmethyl ether (0.090 mL, 0.472 mmol) in 2 CH₃CN/3CHCl₃ (5.0 mL) were reacted to give the desired product (0.0531 g,48.3%). EI-MS m/z 456(M⁺) Rt (2.09 min).

Example 10 Preparation of4-[hydroxy(diphenyl)methyl]-1-{3-[(phenylmethyl)oxy]propyl}-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 4,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0677 g, 0.231 mmol) and3-bromopropyl phenylmethyl ether (0.070 mL, 0.396 mmol) in 2 CH₃CN/3CHCl₃ (4.0 mL) were reacted to give the desired product (0.0663 g,55.2%). EI-MS m/z 442(M⁺) Rt (2.23 min).

Example 11 Preparation of1-{2-[(2,4-dibromophenyl)oxy]ethyl}-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 4,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0557 g, 0.190 mmol) and2-bromoethyl 2,4-dibromophenyl ether (0.110 g, 0.306 mmol) in 2 CH₃CN/3CHCl₃ (4.0 mL) were reacted to give the desired product (0.0525 g,43.8%). EI-MS m/z 572(M⁺) Rt (2.26 min).

Example 12 Preparation of1-(3-bromopropyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0979 g, 0.334 mmol) and1,3-dibromopropane (0.35 mL, 3.448 mmol) in 2 CH₃CN/3 CHCl₃ (15.0 mL)were reacted to give the desired product (0.0712 g, 43.1%). EI-MS m/z415(M⁺) Rt (1.79 min).

Example 13 Preparation of4-[hydroxy(diphenyl)methyl]-1-(tetrahydro-2H-pyran-2-ylmethyl)-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 4,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0677 g, 0.231 mmol) and3-(bromomethyl)tetrahydro-2H-pyran (0.050 mL, 0.390 mmol) in 2 CH₃CN/3CHCl₃ (4.0 mL) were reacted to give the desired product (0.0508 g,50.8%). EI-MS m/z 392(M⁺) Rt (1.84 min).

Example 14 Preparation of1-(1,3-dioxolan-2-ylmethyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 4,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0574 g, 0.196 mmol) and2-(bromomethyl)-1,3-dioxolane (0.040 mL, 0.386 mmol) in 2 CH₃CN/3 CHCl₃(4.0 mL) were reacted to give the desired product (0.0112 g, 12.4%).EI-MS m/z 380(M⁺) Rt (1.64 min).

Example 15 Preparation of1-ethyl-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane bromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0581 g, 0.198 mmol) andbromoethane (0.030 mL, 0.402 mmol) in 2 CH₃CN/3 CHCl₃ (4.0 mL) werereacted to give the desired product (0.0434 g, 54.9%). EI-MS m/z 322(M⁺)Rt (1.56 min).

Example 16 Preparation of4-[hydroxy(diphenyl)methyl]-1-nonyl-1-azoniabicyclo[2.2.2]octane bromide

Following the general procedure outlined in Example 4,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0561 g, 0.191 mmol) and1-bromononane (0.055 mL, 0.288 mmol) in 2 CH₃CN/3 CHCl₃ (4.0 mL) werereacted to give the desired product (0.0435 g, 45.8%). EI-MS m/z 420(M⁺)Rt (2.34 min).

Example 17 Preparation of4-[hydroxy(diphenyl)methyl]-1-(4-penten-1-yl)-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0608 g, 0.207 mmol) and5-bromo-1-pentene (0.045 mL, 0.380 mmol) in 2 CH₃CN/3 CHCl₃ (4.0 mL)were reacted to give the desired product (0.0806 g, 88.6%). EI-MS m/z362(M⁺) Rt (1.88 min).

Example 18 Preparation of4-[hydroxy(diphenyl)methyl]-1-(2-hydroxyethyl)-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0638 g, 0.217 mmol) and2-bromoethanol (0.035 mL, 0.494 mmol) in 2 CH₃CN/3 CHCl₃ (4.0 mL) werereacted to give the desired product (0.0541 g, 60.1%). EI-MS m/z 338(M⁺)Rt (1.42 min).

Example 19 Preparation of1-(5-hexen-1-yl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0637 g, 0.217 mmol) and6-bromo-1-hexene (0.050 mL, 0.373 mmol) in 2 CH₃CN/3 CHCl₃ (5.0 mL) werereacted to give the desired product (0.0664 g, 67.1%). EI-MS m/z 376(M⁺)Rt (1.90 min).

Example 20 Preparation of4-[hydroxy(diphenyl)methyl]-1-methyl-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0638 g, 0.217 mmol) andbromomethane (2.0 M in t-Butylmethyl ether, 0.250 mL, 0.500 mmol) in 2CH₃CN/3 CHCl₃ (4.0 mL) were reacted to give the desired product (0.0739g, 88.0%). EI-MS m/z 308(M⁺) Rt (1.58 min).

Example 21 Preparation of4-[hydroxy(diphenyl)methyl]-1-[2-(methyloxy)ethyl]-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 4,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0597 g, 0.203 mmol) and2-bromoethyl methyl ether (0.030 mL, 0.319 mmol) in 2 CH₃CN/3 CHCl₃ (4.0mL) were reacted to give the desired product (0.0372 g, 42.8%). EI-MSm/z 352(M⁺) Rt (1.69 min).

Example 22 Preparation of1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0916 g, 0.312 mmol) and2-(2-bromoethyl)-1H-isoindole-1,3(2H)-dione (0.130 g, 0.512 mmol) in 2CH₃CN/3 CHCl₃ (4.0 mL) were reacted to give the desired product (0.0881g, 51.8%). EI-MS m/z 467(M⁺) Rt (1.91 min).

Example 23 Preparation of1-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0861 g, 0.293 mmol) and2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione (0.118 g, 0.440 mmol) in 2CH₃CN/3 CHCl₃ (5.0 mL) were reacted to give the desired product (0.1319g, 82.4%). E-MS m/z 481(M⁺) Rt (1.90 min).

Example 24 Preparation of4-[hydroxy(diphenyl)methyl]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0625 g, 0.213 mmol) and(3-bromopropyl)benzene (0.050 mL, 0.329 mmol) in 2 CH₃CN/3 CHCl₃ (5.0mL) were reacted to give the desired product (0.0722 g, 72.2%). EI-MSm/z 412(M⁺) Rt (2.01 min).

Example 25 Preparation of4-[hydroxy(diphenyl)methyl]-1-(2-{[2-(methyloxy)ethyl]oxy}ethyl)-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0665 g, 0.227 mmol) and1-bromo-2-{[2-(methyloxy)ethyl]oxy}ethane (0.05 5 mL, 0.405 mmol) in 2CH₃CN/3 CHCl₃ (4.0 mL) were reacted to give the desired product (0.0843g, 78.8%). EI-MS m/z 396(M⁺) Rt (1.64 min).

Example 26 Preparation of1-[4-(ethyloxy)-4-oxobutyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 4,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0679 g, 0.231 mmol) andethyl 4-bromobutanoate (0.055 mL, 0.524 mmol) in 2 CH₃CN/3 CHCl₃ (4.0mL) were reacted to give the desired product (0.0637 g, 57.9%). EI-MSm/z 408(M⁺) Rt (1.80 min).

Example 27 Preparation of1-azabicyclo[2.2.2]oct-4-yl(di-2-thienyl)methanol

A solution of 2-thienyllithium (1.0M in THF, 9.10 mL, 9.10 mmol) waschilled down to −30° C. under Ar. Ethyl1-azabicyclo[2.2.2]octane-4-carboxylate (0.4196 g, 2.289 mmol) in THF (8mL) was slowly added to the reaction mixture over 20 min. The reactionwas allowed to warm up to room temperature over 16 h. The reaction wasquenched with water and then evaporated to dryness. H₂O and DCM wereadded, causing a light brown solid to crash out. This solid was filteredoff to give the title compound (0.4161 g, 59.5%). EI-MS m/z 306(M+H⁺) Rt(1.35 min).

Example 28 Preparation of4-[hydroxy(di-2-thienyl)methyl]-1-[2-(phenyloxy)ethyl]-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 4,1-azabicyclo[2.2.2]oct-4-yl(di-2-thienyl)methanol (0.0693 g, 0.227 mmol)and 2-bromoethyl phenyl ether (0.056 g, 0.279 mmol) in 1 MeOH/1 CHCl₃(3.0 mL) were reacted to give the desired product (0.0822 g, 74.7%).EI-MS m/z 426(M⁺) Rt (2.00 min).

Example 29 Preparation of4-[hydroxy(di-2-thienyl)methyl]-1-[3-(phenyloxy)propyl]-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 4,1-azabicyclo[2.2.2]oct-4-yl(di-2-thienyl)methanol (0.0578 g, 0.189 mmol)and 3-bromopropyl phenyl ether (0.033 mL, 0.209 mmol) in 1 MeOH/1 CHCl₃(4.0 mL) were reacted to give the desired product (0.0448 g, 45.4%).EI-MS m/z 440(M⁺) Rt (1.94 min).

Example 30 Preparation of4-[hydroxy(di-2-thienyl)methyl]-1-(2-phenylethyl)-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 4,1-azabicyclo[2.2.2]oct-4-yl(di-2-thienyl)methanol (0.0658 g, 0.215 mmol)and (2-bromoethyl)benzene (0.050 mL, 0.366 mmol) in 1 MeOH/1 CHCl₃ (4.0mL) were reacted to give the desired product (0.051 4 g, 48.9%). EI-MSm/z 410(M⁺) Rt (1.83 min).

Example 31 Preparation of4-[hydroxy(di-2-thienyl)methyl]-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 4,1-azabicyclo[2.2.2]oct-4-yl(di-2-thienyl)methanol (0.0688 g, 0.225 mmol)and (3-bromopropyl)benzene (0.070 mL, 0.460 mmol) in 1 MeOH/1 CHCl₃ (4.0mL) were reacted to give the desired product (0.0685 g, 62.3%). EI-MSm/z 424(M⁺) Rt (1.97 min).

Example 32 Preparation of1-butyl-4-[hydroxy(di-3-thienyl)methyl]-1-azoniabicyclo[2.2.2]octanebromide

A solution of n-Butyl lithium (2.5M in hexanes, 5.0 mL, 12.5 mmol) waschilled to −78° C. under Ar. 3-Bromothiophene (1.15 mL, 12.3 mmol)dissolved in ethyl ether (4.0 mL) was slowly added to the reactionmixture. The reaction was stirred for 30 min and then ethyl1-azabicyclo[2.2.2]octane-4-carboxylate (0.7640 g, 4.16 mmol) inTHF/Et₂O (4 mL/4 mL) was added. The reaction was allowed to warm up from−78° C. to room temperature over 16 h then slowly quenched with water.The reaction was concentrated and the resulting brown solid was taken upin water and DCM. The organic phase was separated, dried over MgSO₄,filtered and concentrated under vacuum to give a brown solid. The solidwas dissolved in DMSO and purified by preparatory HPLC to give the titlecompound (0.1736 g, 9.4%). EI-MS m/z 362(M⁺) Rt (1.73 min).

Example 33 Preparation of1-azabicyclo[2.2.2]oct-4-yl(di-3-thienyl)methanol.

A solution of t-Butyl lithium (1.7M in pentanes, 5.8 mL, 9.86 mmol) waschilled to −78° C. under Ar. 3-Bromothiophene (0.46 mL, 4.90 mmol)dissolved in THF (4.0 mL) was slowly added to the reaction mixture over6 min. The reaction was stirred for 30 min and then ethyl1-azabicyclo[2.2.2]octane-4-carboxylate (0.3132 g, 1.71 mmol) in THF (4mL) was added. The reaction was allowed to warm up from −78° C. to roomtemperature over 16 h. After 14 hours, the reaction was slowly quenchedwith water. EtOAc was added, causing a grey solid to crash out. Thesolid was filtered off to give the title compound (0.3375 g, 64.6%).EI-MS m/z 306(M+H)⁺ Rt (1.27 min).

Example 34 Preparation of4-[hydroxy(di-3-thienyl)methyl]-1-[2-(phenyloxy)ethyl]-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 4,1-azabicyclo[2.2.2]oct-4-yl(di-3-thienyl)methanol (0.0787 g, 0.258 mmol)and 2-bromoethyl phenyl ether (0.0839 g, 0.417 mmol) in 2MeOH/3 CHCl₃/2CH₃CN (5.0 mL) were reacted to give the desired product (0.0709 g,54.5%). EI-MS m/z 426(M⁺) Rt (1.85 min).

Example 35 Preparation of4-[hydroxy(di-3-thienyl)methyl]-1-[3-(phenyloxy)propyl]-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 4,1-azabicyclo[2.2.2]oct-4-yl(di-3-thienyl)methanol (0.0808 g, 0.264 mmol)and 3-bromopropyl phenyl ether (0.070 mL, 0.444 mmol) in 2MeOH/3 CHCl₃/2CH₃CN (5.0 mL) were reacted to give the desired product (0.0613 g,44.7%). EI-MS m/z 440(M⁺) Rt (2.05 min).

Example 36 Preparation of1-butyl-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane bromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0496 g, 0.169 mmol) and1-bromobutane (0.030 mL, 0.279 mmol) in 2 CH₃CN/3 CHCl₃ (4.0 mL) werereacted to give the desired product (0.0509 g, 70.7%). EI-MS m/z 350(M⁺)Rt (1.83 min).

Example 37 Preparation of1-hexyl-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane bromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0498 g, 0.170 mmol) and1-bromohexane (0.040 mL, 0.285 mmol) in 2 CH₃CN/3 CHCl₃ (4.0 mL) werereacted to give the desired product (0.0562 g, 73.0%). EI-MS m/z 378(M⁺)Rt (2.09 min).

Example 38 Preparation of4-[hydroxy(diphenyl)methyl]-1-propyl-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0518 g, 0.176 mmol) and1-bromopropane (0.030 mL, 0.330 mmol) in 2 CH₃CN/3 CHCl₃ (4.0 mL) werereacted to give the desired product (0.0548 g, 75.1%). EI-MS m/z 336(M⁺)Rt (1.97 min).

Example 39 Preparation of4-[hydroxy(diphenyl)methyl]-1-(3-{[2-(methyloxy)phenyl]oxy}propyl)-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0467 g, 0.159 mmol) and1-[(3-bromopropyl)oxy]-2-(methyloxy)benzene (0.0541 g, 0.221 mmol) in 2CH₃CN/3 CHCl₃ (4.0 mL) were reacted to give the desired product (0.0625g, 73.5%). EI-MS m/z 458(M⁺) Rt (1.96 min).

Example 40 Preparation of4-[hydroxy(diphenyl)methyl]-1-{3-[(2-hydroxyphenyl)oxy]propyl}-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0505 g, 0.172 mmol) and2-[(3-bromopropyl)oxy]phenol (0.0547 g, 0.236 mmol) in 2 CH₃CN/3 CHCl₃(4.0 mL) were reacted to give the desired product (0.0675 g, 75.0%).EI-MS m/z 444(M⁺) Rt (1.91 min).

Example 41 Preparation of4-[hydroxy(diphenyl)methyl]-1-[3-(2-naphthalenyloxy)propyl]-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0472 g, 0.160 mmol) and3-bromopropyl 2-naphthalenyl ether (0.0618 g, 0.233 mmol) in 2 CH₃CN/3CHCl₃ (4.0 mL) were reacted to give the desired product (0.0567 g,63.7%). EI-MS m/z 478(M⁺) Rt (2.22 min).

Example 42 Preparation of1-{3-[(3-chlorophenyl)oxy]propyl}-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0479 g, 0.163 mmol) and3-bromopropyl 3-chlorophenyl ether (0.0552 g, 0.221 mmol) in 2 CH₃CN/3CHCl₃ (4.0 mL) were reacted to give the desired product (0.0655 g,74.4%). EI-MS m/z 462(M⁺) Rt (2.17 min).

Example 43 Preparation of1-{3-[(4-bromophenyl)oxy]propyl}-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0486 g, 0.165 mmol) and4-bromophenyl 3-bromopropyl ether (0.0630 g, 0.214 mmol) in 2 CH₃CN/3CHCl₃ (4.0 mL) were reacted to give the desired product (0.0731 g,75.4%). EI-MS m/z 506(M⁺) Rt (2.18 min).

Example 44 Preparation of4-[hydroxy(diphenyl)methyl]-1-{3-[(4-nitrophenyl)oxy]propyl}-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0468 g, 0.159 mmol) and3-bromopropyl 4-nitrophenyl ether (0.0550 g, 0.211 mmol) in 2 CH₃CN/3CHCl₃ (4.0 mL) were reacted to give the desired product (0.0590 g,67.0%). EI-MS m/z 473(M⁺) Rt (2.06 min).

Example 45 Preparation of4-[hydroxy(diphenyl)methyl]-1-[3-({2-[(phenylmethyl)oxy]phenyl}oxy)propyl]-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0492 g, 0.168 mmol) and1-[(3-bromopropyl)oxy]-2-[(phenylmethyl)oxy]benzene (0.0706 g, 0.220mmol) in 2 CH₃CN/3 CHCl₃ (4.0 mL) were reacted to give the desiredproduct (0.0735 g, 71.4%). EI-MS m/z 533(M⁺) Rt (2.25 min).

Example 46 Preparation of1-{3-[(2-bromophenyl)oxy]propyl}-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0472 g, 0.161 mmol) and2-bromophenyl 3-bromopropyl ether (0.0648 g, 0.220 mmol) in 2 CH₃CN/3CHCl₃ (4.0 mL) were reacted to give the desired product (0.0703 g,74.8%). EI-MS m/z 507(M⁺) Rt (2.18 min).

Example 47 Preparation of4-[hydroxy(diphenyl)methyl]-1-[3-({4-[(phenylmethyl)oxy]phenyl}oxy)propyl]-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0479 g, 0.163 mmol) and1-[(3-bromopropyl)oxy]-4-[(phenylmethyl)oxy]benzene (0.0730 g, 0.227mmol) in 2 CH₃CN/3 CHCl₃ (4.0 mL) were reacted to give the desiredproduct (0.0833 g, 83.3%). EI-MS m/z 534(M⁺) Rt (2.31 min).

Example 48 Preparation of4-[hydroxy(diphenyl)methyl]-1-[3-(methyloxy)propyl]-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0632 g, 0.215 mmol) and3-bromopropyl methyl ether (0.0461 g, 0.301 mmol) in 2 CH₃CN/3 CHCl₃(4.0 mL) were reacted to give the desired product (0.0826 g, 86.0%).EI-MS m/z 366(M⁺) Rt (1.55 min).

Example 49 Preparation of4-[hydroxy(diphenyl)methyl]-1-(2-propen-1-yl)-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0577 g, 0.197 mmol) and3-bromo-1-propene (0.025 mL, 0.289 mmol) in 2 CH₃CN/3 CHCl₃ (4.0 mL)were reacted to give the desired product (0.0646 g, 79.8%). EI-MS m/z334(M⁺) Rt (1.54 min).

Example 50 Preparation of4-[hydroxy(diphenyl)methyl]-1-(3-{[4-(methyloxy)phenyl]oxy}propyl)-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0483 g, 0.164 mmol) and1-[(3-bromopropyl)oxy]-4-(methyloxy)benzene (0.052 g, 0.21 mmol) in 2CH₃CN/3 CHCl₃ (4.0 mL) were reacted to give the desired product (0.0687g, 77.5%). EI-MS m/z 458(M⁺) Rt (2.03 min).

Example 51 Preparation of[1-(2-aminoethyl)-1-azoniabicyclo[2.2.2]oct-4-yl](diphenyl)methanolatetrifluoroacetate

To a solution of1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octanebromide (0.078 g, 0.142 mmol) in EtOH (4.0 mL) was added hydrazine (0.25mL, 7.96 mmol). The solution was stirred at room temperature for 16 hand then filtered. The filtrate was concentrated and taken up in 2.5 mLof DMSO and purified by preparatory HPLC (with TFA) to give the titlecompound (0.0200 g, 31.2%). EI-MS m/z 338(M⁺) Rt (1.28 min).

Example 52 Preparation of4-[bis(4-fluorophenyl)(hydroxy)methyl]-1-[3-(phenyloxy)propyl]-1-azoniabicyclo[2.2.2]octanebromide 1-azabicyclo[2.2.2]oct-4-yl[bis(4-fluorophenyl)]methanol

A solution of 4-fluorophenylmagnesiumbromide (1.0 M in THF, 4.4 mL, 4.4mmol) was chilled down to 0° C. under Ar. Ethyl1-azabicyclo[2.2.2]octane-4-carboxylate (0.1973 g, 1.08 mmol) in THF (4mL) was slowly added to the reaction mixture at 0° C. over 20 min. Thereaction was allowed to warm up to room temperature and then heated at60° C. for 16 h. The reaction was chilled in an ice bath, quenched withsaturated NH₄Cl, and concentrated under vacuum. The resulting residuewas treated with H₂O and extracted with EtOAc. The combined organiclayers were dried with MgSO₄, filtered, and concentrated under vacuum toyield the desired product (0.3152 g, 88.9%). EI-MS m/z 330(M+H⁺) Rt(1.65 min).

4-[bis(4-fluorophenyl)(hydroxy)methyl]-1-[3-(phenyloxy)propyl]-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl[bis(4-fluorophenyl)]methanol (0.0538 g,0.163 mmol) and 3-bromopropyl phenyl ether (0.0386 mL, 0.245 mmol) in 2CH₃CN/3 CHCl₃ (4.0 mL) were reacted to give the desired product (0.058g, 65.2%). EI-MS m/z 464(M⁺) Rt (2.16 min).

Example 53 Preparation of4-[bis(4-fluorophenyl)(hydroxy)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl[bis(4-fluorophenyl)]methanol (0.0489 g,0.148 mmol) and 2-bromoethyl phenylmethyl ether (0.0352 mL, 0.222 mmol)in 2 CH₃CN/3 CHCl₃ (4.0 mL) were reacted to give the desired product(0.0534 g, 66.1%). EI-MS m/z 464(M⁺) Rt (1.99 min).

Example 54 Preparation of4-(hydroxy{bis[3-(methyloxy)phenyl]}methyl)-1-[3-(phenyloxy)propyl]-1-azoniabicyclo[2.2.2]octanebromide 1-azabicyclo[2.2.2]oct-4-yl{bis[3-(methyloxy)phenyl]}methanol

A solution of 3-(methyloxy)phenylmagnesiumbromide (1.0 M in THF, 3.3 mL,3.3 mmol) was chilled down to 0° C. under Ar. Ethyl1-azabicyclo[2.2.2]octane-4-carboxylate (0.1608 g, 0.877 mmol) in THF (4mL) was slowly added to the reaction mixture at 0° C. over 20 min. Thereaction was allowed to warm up to room temperature and then heated at60° C. for 16 h. The reaction was chilled in an ice bath, quenched withsaturated NH₄Cl, and concentrated under vacuum. The resulting residuewas treated with H₂O and extracted with EtOAc. The combined organiclayers were dried with MgSO₄, filtered, and concentrated under vacuum toyield the desired product (0.2881 g, 92.9%). EI-MS m/z 354(M+H⁺) Rt(1.46 min).

4-(hydroxy{bis[3-(methyloxy)phenyl]}methyl)-1-[3-(phenyloxy)propyl]-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl{bis[3-(methyloxy)phenyl]}methanol (0.0506 g,0.143 mmol) and 3-bromopropyl phenyl ether (0.0338 mL, 0.214 mmol) in 2CH₃CN/3 CHCl₃ (4.0 mL) were reacted to give the desired product (0.027g, 33.2%). EI-MS m/z 488(M⁺) Rt (2.02 min).

Example 55 Preparation of4-(hydroxy{bis[3-(methyloxy)phenyl]}methyl)-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl{bis[3-(methyloxy)phenyl]}methanol (0.0538 g,0.152 mmol) and 2-bromoethyl phenylmethyl ether (0.0361 mL, 0.228 mmol)in 2 CH₃CN/3 CHCl₃ (4.0 mL) were reacted to give the desired product(0.0292 g, 33.8%). EI-MS m/z 488(M⁺) Rt (2.03 min).

Example 56 Preparation of4-(hydroxy{bis[4-(methyloxy)phenyl]}methyl)-1-[3-(phenyloxy)propyl]-1-azoniabicyclo[2.2.2]octanebromide 1-azabicyclo[2.2.2]oct-4-yl{bis[4-(methyloxy)phenyl]}methanol

A solution of 4-(methyloxy)phenylmagnesiumbromide (0.5 M in THF, 6.5 mL,3.25 mmol) was chilled down to 0° C. under Ar. Ethyl1-azabicyclo[2.2.2]octane-4-carboxylate (0.1587 g, 0.866 mmol) in THF (4mL) was slowly added to the reaction mixture at 0° C. over 20 min. Thereaction was allowed to warm up to room temperature and then heated at60° C. for 16 h. The reaction was chilled in an ice bath, quenched withsaturated NH₄Cl, and concentrated under vacuum. The resulting residuewas treated with H₂O and extracted with EtOAc. The combined organiclayers were dried with MgSO₄, filtered, and concentrated under vacuum toyield the desired product (0.273 g, 89.0%). EI-MS m/z 354(M+H⁺) Rt (1.74min).

4-(hydroxy{bis[3-(methyloxy)phenyl]}methyl)-1-[3-(phenyloxy)propyl]-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl{bis[4-(methyloxy)phenyl]}methanol (0.0525 g,0.148 mmol) and 3-bromopropyl phenyl ether (0.0351 mL, 0.222 mmol) in 2CH₃CN/3 CHCl₃ (4.0 mL) were reacted to give the desired product (0.0515g, 61.0%). EI-MS m/z 488(M⁺) Rt (2.04 min).

Example 57 Preparation of4-(hydroxy{bis[4-(methyloxy)phenyl]}methyl)-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl{bis[4-(methyloxy)phenyl]}methanol (0.0498 g,0.141 mmol) and 2-bromoethyl phenylmethyl ether (0.0334 mL, 0.211 mmol)in 2 CH₃CN/3 CHCl₃ (4.0 mL) were reacted to give the desired product(0.0374 g, 46.7%). EI-MS m/z 488(M⁺) Rt (1.94 min).

Example 58 Preparation of4-[bis(3-fluorophenyl)(hydroxy)methyl]-1-[3-(phenyloxy)propyl]-1-azoniabicyclo[2.2.2]octanebromide 1-azabicyclo[2.2.2]oct-4-yl[bis(3-fluorophenyl)]methanol

A solution of 3-fluorophenylmagnesiumbromide (1.0 M in THF, 3.3 mL, 3.3mmol) was chilled down to 0° C. under Ar. Ethyl1-azabicyclo[2.2.2]octane-4-carboxylate (0.1756 g, 0.958 mmol) in THF (4mL) was slowly added to the reaction mixture at 0° C. over 20 min. Thereaction was allowed to warm up to room temperature and then heated at60° C. for 16 h. The reaction was chilled in an ice bath, quenched withsaturated NH₄Cl, and concentrated under vacuum. The resulting residuewas treated with H₂O and extracted with EtOAc. The combined organiclayers were dried with MgSO₄, filtered, and concentrated under vacuum toyield the desired product (0.242 g, 76.7%). EI-MS m/z 330(M+H⁺) Rt (1.45min).

4-(hydroxy{bis[3-(methyloxy)phenyl]}methyl)-1-[3-(phenyloxy)propyl]-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl[bis(3-fluorophenyl)]methanol (0.0515 g,0.156 mmol) and 3-bromopropyl phenyl ether (0.0370 mL, 0.234 mmol) in 2CH₃CN/3 CHCl₃ (4.0 mL) were reacted to give the desired product (0.0381g, 44.8%). EI-MS m/z 464(M⁺) Rt (2.01 min).

Example 59 Preparation of4-[bis(3-fluorophenyl)(hydroxy)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl[bis(3-fluorophenyl)]methanol (0.0507 g,0.154 mmol) and 2-bromoethyl phenylmethyl ether (0.0365 mL, 0.230 mmol)in 2 CH₃CN/3 CHCl₃ (4.0 mL) were reacted to give the desired product(0.0362 g, 43.2%). EI-MS m/z 464(M⁺) Rt (2.02 min).

Example 60 Preparation of4-{hydroxy[bis(3-methylphenyl)]methyl}-1-[3-(phenyloxy)propyl]-1-azoniabicyclo[2.2.2]octanebromide 1-azabicyclo[2.2.2]oct-4-yl[bis(3-methylphenyl)]methanol

A solution of 3-methylphenylmagnesiumbromide (1.0 M in THF, 3.3 mL, 3.3mmol) was chilled down to 0° C. under Ar. Ethyl1-azabicyclo[2.2.2]octane-4-carboxylate (0.1484 g, 0.810 mmol) in THF (4mL) was slowly added to the reaction mixture at 0° C. over 20 min. Thereaction was allowed to warm up to room temperature and then heated at60° C. for 16 h. The reaction was chilled in an ice bath, quenched withsaturated NH₄Cl, and concentrated under vacuum. The resulting residuewas treated with H₂O and extracted with EtOAc. The combined organiclayers were dried with MgSO₄, filtered, and concentrated under vacuum toyield the desired product (0.1806 g, 69.4%). EI-MS m/z 322(M+H⁺) Rt(1.54 min).

4-(hydroxy{bis[3-(methyloxy)phenyl]}methyl)-1-[3-(phenyloxy)propyl]-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl[bis(3-methylphenyl)]methanol (0.0487 g,0.151 mmol) and 3-bromopropyl phenyl ether (0.0358 mL, 0.227 mmol) in 2CH₃CN/3 CHCl₃ (4.0 mL) were reacted to give the desired product (0.0284g, 34.9%). EI-MS m/z 456(M⁺) Rt (2.14 min).

Example 61 Preparation of4-{hydroxy[bis(3-methylphenyl)]methyl}-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 4,1-azabicyclo[2.2.2]oct-4-yl[bis(3-methylphenyl)]methanol (0.0496 g,0.154 mmol) and 2-bromoethyl phenylmethyl ether (0.0364 mL, 0.230 mmol)in 2 CH₃CN/3 CHCl₃ (4.0 mL) were reacted to give the desired product(0.0091 g, 11.0%). EI-MS m/z 456(M⁺) Rt (2.20 min).

Example 62 Preparation of4-{hydroxy[bis(4-methylphenyl)]methyl}-1-[3-(phenyloxy)propyl]-1-azoniabicyclo[2.2.2]octanebromide 1-azabicyclo[2.2.2]oct-4-yl[bis(4-methylphenyl)]methanol

A solution of 4-methylphenylmagnesiumbromide (1.0 M in THF, 3.3 mL, 3.3mmol) was chilled down to 0° C. under Ar. Ethyl1-azabicyclo[2.2.2]octane-4-carboxylate (0.1509 g, 0.823 mmol) in THF (4mL) was slowly added to the reaction mixture at 0° C. over 20 min. Thereaction was allowed to warm up to room temperature and then heated at60° C. for 16 h. The reaction was chilled in an ice bath, quenched withsaturated NH₄Cl, and concentrated under vacuum. The resulting residuewas treated with H₂O and extracted with EtOAc. The combined organiclayers were dried with MgSO₄, filtered, and concentrated under vacuum toyield the desired product (0.2291 g, 86.6%). EI-MS m/z 322(M+H⁺) Rt(1.57 min).

4-(hydroxy{bis[3-(methyloxy)phenyl]}methyl)-1-[3-(phenyloxy)propyl]-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl[bis(4-methylphenyl)]methanol (0.0618 g,0.192 mmol) and 3-bromopropyl phenyl ether (0.0454 mL, 0.288 mmol) in 2CH₃CN/3 CHCl₃ (4.0 mL) were reacted to give the desired product (0.0427g, 41.5%). EI-MS m/z 456(M⁺) Rt (1.99 min).

Example 63 Preparation of4-{hydroxy[bis(4-methylphenyl)]methyl}-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl[bis(4-methylphenyl)]methanol (0.0525 g,0.163 mmol) and 2-bromoethyl phenylmethyl ether (0.0387 mL, 0.245 mmol)in 2 CH₃CN/3 CHCl₃ (4.0 mL) were reacted to give the desired product(0.0465 g, 53.1%). EI-MS m/z 456(M⁺) Rt (2.09 min).

Example 64 Preparation of4-[hydroxy(di-2-naphthalenyl)methyl]-1-[3-(phenyloxy)propyl]-1-azoniabicyclo[2.2.2]octanebromide 1-azabicyclo[2.2.2]oct-4-yl(di-2-naphthalenyl)methanol

A solution of (2-naphthalenyl)magnesiumbromide (0.5 M in THF, 6.5 mL,3.25 mmol) was chilled down to 0° C. under Ar. Ethyl1-azabicyclo[2.2.2]octane-4-carboxylate (0.1597 g, 0.871 mmol) in THF (4mL) was slowly added to the reaction mixture at 0° C. over 20 min. Thereaction was allowed to warm up to room temperature and then heated at60° C. for 16 h. The reaction was chilled in an ice bath, quenched withsaturated NH₄Cl, and concentrated under vacuum. The resulting residuewas treated with H₂O and extracted with EtOAc. The combined organiclayers were dried with MgSO₄, filtered, and concentrated under vacuum toyield the desired product (0.265 g, 77.3%). EI-MS m/z 394(M+H⁺) Rt (1.90min).

4-(hydroxy{bis[3-(methyloxy)phenyl]}methyl)-1-[3-(phenyloxy)propyl]-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl(di-2-naphthalenyl)methanol (0.0547 g, 0.139mmol) and 3-bromopropyl phenyl ether (0.0329 mL, 0.209 mmol) in 2CH₃CN/3 CHCl₃ (4.0 mL) were reacted to give the desired product (0.0268g, 31.7%). EI-MS m/z 528(M⁺) Rt (2.88 min).

Example 65 Preparation of4-[hydroxy(di-2-naphthalenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl(di-2-naphthalenyl)methanol (0.063.7 g, 0.162mmol) and 2-bromoethyl phenylmethyl ether (0.0384 mL, 0.243 mmol) in 2CH₃CN/3 CHCl₃ (4.0 mL) were reacted to give the desired product (0.0246g, 25.0%). EI-MS m/z 528(M⁺) Rt (2.36 min).

Example 66 Preparation of1-{3-[(2-fluorophenyl)oxy]propyl}-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octanebromide 3-bromopropyl 2-fluorophenyl ether

To a solution of 2-fluorophenol (0.040 mL, 0.448 mmol) in acetonitrile(4 mL) was added 1,3-dibromopropane (0.450 mL, 4.43 mmol) followed byCs₂CO₃ (0.232 g, 0.713 mmol). The reaction mixture was stirred for 24 hand then concentrated under vacuum. The resulting residue was treatedwith H₂O (4 mL) and extracted with DCM (8 mL). The organic layer wasdried through a phase separator and concentrated under vacuum. Theresidue was taken up in DMSO and purified by preparatory HPLC (withoutTFA) to give the title compound (0.0274 g, 26.2%). EI-MS Rt (2.24 min).

1-{3-[(2-fluorophenyl)oxy]propyl}-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0282 g, 0.0960 mmol)and 3-bromopropyl 2-fluorophenyl ether (0.0274 g, 0.118 mmol) in 2CH₃CN/3 CHCl₃ (4.0 mL) were reacted to give the desired product (0.0345g, 68.3%). EI-MS m/z 446(M⁺) Rt (1.96 min).

Example 67 Preparation of1-{3-[(3-fluorophenyl)oxy]propyl}-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octanebromide 3-bromopropyl 3-fluorophenyl ether

To a solution of 3-fluorophenol (0.040 mL, 0.448 mmol) in acetonitrile(4 mL) was added 1,3-dibromopropane (0.450 mL, 4.43 mmol) followed byCs₂CO₃ (0.246 g, 0.756 mmol). The reaction mixture was stirred for 24 hand then concentrated under vacuum. The resulting residue was treatedwith H₂O (4 mL) and extracted with DCM (8 mL). The organic layer wasdried through a phase separator and concentrated under vacuum. Theresidue was taken up in DMSO and purified by preparatory HPLC (withoutTFA) to give the title compound (0.0137 g, 13.2%). EI-MS Rt (2.28 min).

1-{3-[(3-fluorophenyl)oxy]propyl}-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0137 g, 0.0467 mmol)and 3-bromopropyl 3-fluorophenyl ether (0.0137 g, 0.0588 mmol) in 2CH₃CN/3 CHCl₃ (4.0 mL) were reacted to give the desired product (0.0130g, 53.1%). EI-MS m/z 446(M⁺) Rt (2.03 min).

Example 68 Preparation of1-{3-[(4-fluorophenyl)oxy]propyl}-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octanebromide 3-bromopropyl 4-fluorophenyl ether

To a solution of 4-fluorophenol (0.0567 g, 0.506 mmol) in acetonitrile(4 mL) was added 1,3-dibromopropane (0.520 mL, 5.12 mmol) followed byCs₂CO₃ (0.252 g, 0.774 mmol). The reaction mixture was stirred for 24 hand then concentrated under vacuum. The resulting residue was treatedwith H₂O (4 mL) and extracted with DCM (8 mL). The organic layer wasdried through a phase separator and concentrated under vacuum. Theresidue was taken up in DMSO and purified by preparatory HPLC (withoutTFA) to give the title compound (0.0173 g, 14.7%). EI-MS Rt (2.25 min).

1-{3-[(4-fluorophenyl)oxy]propyl}-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0182 g, 0.0621 mmol)and 3-bromopropyl 4-fluorophenyl ether (0.0173 g, 0.0742 mmol) in 2CH₃CN/3 CHCl₃ (4.0 mL) were reacted to give the desired product (0.0143g, 43.7%). EI-MS m/z 446(M⁺) Rt (1.96 min).

Example 69 Preparation of1-[3-(3-biphenylyloxy)propyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octanebromide 3-biphenylyl 3-bromopropyl ether

To a solution of 3-biphenylol (0.0574 g, 0.337 mmol) in acetonitrile (4mL) was added 1,3-dibromopropane (0.340 mL, 3.35 mmol) followed byCs₂CO₃ (0.172 g, 0.529 mmol). The reaction mixture was stirred for 24 hand then concentrated under vacuum. The resulting residue was treatedwith H₂O (4 mL) and extracted with DCM (8 mL). The organic layer wasdried through a phase separator and concentrated under vacuum. Theresidue was taken up in DMSO and purified by preparatory HPLC (withoutTFA) to give the title compound (0.0568 g, 57.8%). EI-MS Rt (2.59 min).

1-[3-(3-biphenylyloxy)propyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0433 g, 0.148 mmol) and3-biphenylyl 3-bromopropyl ether (0.0568 g, 0.196 mmol) in 2 CH₃CN/3CHCl₃ (4.0 mL) were reacted to give the desired product (0.0610 g,70.6%). EI-MS m/z 504(M⁺) Rt (2.37 min).

Example 70 Preparation of1-[3-(4-biphenylyloxy)propyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octanebromide 4-biphenylyl 3-bromopropyl ether

To a solution of 4-biphenylol (0.0514 g, 0.302 mmol) in acetonitrile (4mL) was added 1,3-dibromopropane (0.310 mL, 3.05 mmol) followed byCs₂CO₃ (0.154 g, 0.472 mmol). The reaction mixture was stirred for 24 hand then concentrated under vacuum. The resulting residue was treatedwith H₂O (4 mL) and extracted with DCM (8 mL). The organic layer wasdried through a phase separator and concentrated under vacuum. Theresidue was taken up in DMSO and purified by preparatory HPLC (withoutTFA) to give the title compound (0.0562 g, 64.0%). EI-MS Rt (2.62 min).

1-[3-(4-biphenylyloxy)propyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0437 g, 0.144 mmol) and4-biphenylyl 3-bromopropyl ether (0.0562 g, 0.194 mmol) in 2 CH₃CN/3CHCl₃ (4.0 mL) were reacted to give the desired product (0.0655 g,75.2%). EI-MS m/z 504(M⁺) Rt (2.24 min).

Example 71 Preparation of4-[hydroxy(diphenyl)methyl]-1-{3-[(3-nitrophenyl)oxy]propyl}-1-azoniabicyclo[2.2.2]octanebromide 3-bromopropyl 3-nitrophenyl ether

To a solution of 3-nitrophenol (0.0689 g, 0.495 mmol) in acetonitrile (4mL) was added 1,3-dibromopropane (0.500 mL, 3.05 mmol) followed byCs₂CO₃ (0.244 g, 0.748 mmol). The reaction mixture was stirred for 24 hand then concentrated under vacuum. The resulting residue was treatedwith H₂O (4 mL) and extracted with DCM (8 mL). The organic layer wasdried through a phase separator and concentrated under vacuum. Theresidue was taken up in DMSO and purified by preparatory HPLC (withoutTFA) to give the title compound (0.0730 g, 56.6%). EI-MS Rt (2.20 min).

4-[hydroxy(diphenyl)methyl]-1-{3-[(3-nitrophenyl)oxy]propyl}-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0608 g, 0.207 mmol) and3-bromopropyl 3-nitrophenyl ether (0.0730 g, 0.281 mmol) in 2 CH₃CN/3CHCl₃ (4.0 mL) were reacted to give the desired product (0.0942 g,82.2%). EI-MS m/z 474(M⁺) Rt (2.04 min).

Example 72 Preparation of4-[hydroxy(diphenyl)methyl]-1-{3-[(2-methylphenyl)oxy]propyl}-1-azoniabicyclo[2.2.2]octanebromide 3-bromopropyl 2-methylphenyl ether

To a solution of 2-methylphenol (0.0954 g, 0.924 mmol) in acetonitrile(4 mL) was added 1,3-dibromopropane (1.00 mL, 9.85 mmol) followed byCs₂CO₃ (0.469 g, 1.44 mmol). The reaction mixture was stirred for 24 hand then concentrated under vacuum. The resulting residue was treatedwith H₂O (4 mL) and extracted with DCM (8 mL). The organic layer wasdried through a phase separator and concentrated under vacuum. Theresidue was taken up in DMSO and purified by preparatory HPLC (withoutTFA) to give the title compound (0.0934 g, 44.1%). EI-MS Rt (2.45 min).

4-[hydroxy(diphenyl)methyl]-1-{3-[(2-methylphenyl)oxy]propyl}-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0447 g, 0.152 mmol) and3-bromopropyl 2-methylphenyl ether (0.0934 g, 0.407 mmol) in 2 CH₃CN/3CHCl₃ (4.0 mL) were reacted to give the desired product (0.0586 g,76.5%). EI-MS m/z 442(M⁺) Rt (2.17 min).

Example 73 Preparation of1-(3-{[3-(diethylamino)phenyl]oxy}propyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octanebromide 3-[(3-bromopropyl)oxy]-N,N-diethylaniline

To a solution of 3-(diethylamino)phenol (0.0104 g, 0.631 mmol) inacetonitrile (4 mL) was added 1,3-dibromopropane (0.640 mL, 6.30 mmol)followed by Cs₂CO₃ (0.313 g, 0.961 mmol). The reaction mixture wasstirred for 24 h and then concentrated under vacuum. The resultingresidue was treated with H₂O (4 mL) and extracted with DCM (8 mL). Theorganic layer was dried through a phase separator and concentrated undervacuum. The residue was taken up in DMSO and purified by preparatoryHPLC (without TFA) to give the title compound (0.0314 g, 17.4%). EI-MSm/z 286(M+H⁺) Rt (1.59 min).

1-(3-{[3-(diethylamino)phenyl]oxy}propyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0257 g, 0.0876 mmol)and 3-[(3-bromopropyl)oxy]-N,N-diethylaniline (0.0314 g, 0.110 mmol) in2 CH₃CN/3 CHCl₃ (4.0 mL) were reacted to give the desired product(0.032.0 g, 63.0%). EI-MS m/z 500(M⁺) Rt (1.58 min).

Example 74 Preparation of1-{3-[(4-cyanophenyl)oxy]propyl}-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octanebromide 4-[(3-bromopropyl)oxy]benzonitrile

To a solution of 4-hydroxybenzonitrile (0.109 g, 0.913 mmol) inacetonitrile (4 mL) was added 1,3-dibromopropane (0.930 mL, 9.16 mmol)followed by Cs₂CO₃ (0.439 g, 1.35 mmol). The reaction mixture wasstirred for 24 h and then concentrated under vacuum. The resultingresidue was treated with H₂O (4 mL) and extracted with DCM (8 mL). Theorganic layer was dried through a phase separator and concentrated undervacuum. The residue was taken up in DMSO and purified by preparatoryHPLC (without TFA) to give the title compound (0.156 g, 71.4%). EI-MS Rt(2.10 min).

1-{3-[(4-cyanophenyl)oxy]propyl}-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octanebromide

Following the general procedure outlined in Example 3,1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0520 g, 0.177 mmol) and4-[(3-bromopropyl)oxy]benzonitrile (0.156 g, 0.652 mmol) in 2 CH₃CN/3CHCl₃ (4.0 mL) were reacted to give the desired product (0.0726 g,76.8%). EI-MS m/z 453(M⁺) Rt (1.86 min).

Example 75 Preparation of4-[hydroxy(diphenyl)methyl]-1-[2-({[3-(methyloxy)phenyl]methyl}oxy)ethyl]-1-azoniabicyclo[2.2.2]octanebromide 2-({[3-(methyloxy)phenyl]methyl}oxy)ethanol

Ethylene glycol (0.084 mL, 1.5 mmol) was added to NaH (38 mg, 1.52 mmol,95% in oil) in THF (3 mL) (caution: exotherm). m-Methoxybenzyl chloride(0.21 mL, 1.5 mmol) was added to the reaction, and the residualm-methoxybenzyl chloride was transferred to the reaction tube withadditional THF (1 mL). (Bu)₄NI (55 mg, 0.15 mmol) was then added, andthe reaction was heated at 60° C. for 18 h and then cooled to roomtemperature for 4 h. H₂O (2 mL) and EtOAc (2 mL) were added, and thelayers were separated via pipette. The aqueous layer was extracted withEtOAc (1×1 mL), and the combined organic layers were concentrated. Thecrude product was purified on a Biotage 12+M cartridge (8 g silica)eluting with 30% EtOAc/hexanes at 5 mL/min to give the title compound(114 mg, 42%). The product was characterized by ¹H NMR (400 MHz) inCDCl₃.

1-{[(2-bromoethyl)oxy]methyl}-3-(methyloxy)benzene

A solution of N-bromosuccinimide (272 mg, 1.53 mmol) in DCM (2.5 mL) wasadded resin-bound triphenylphosphine (510 mg, 1.53 mEquiv, Fluka) in DCM(2.5 mL). The reaction was stirred at room temperature for 10 min. Asolution of 2-({[3-(methyloxy)phenyl]methyl}oxy)ethanol (114 mg, 0.626mmol) in DCM (1.5 mL) was added to the reaction, and the residualalcohol was transferred with additional DCM (1.5 mL). The reactionvessel was wrapped in aluminum foil and stirred at rt for 20 h. Thereaction was filtered through a SPE cartridge (5 g silica) eluting withthe following 10 mL fractions: DCM (fraction 1), 30% EtOAc/hexanes(fraction 2), and 50% EtOAc/hexanes (fraction 3) to give the titlecompound (160 mg). The product was characterized by ¹H NMR (400 MHz) inCDCl₃.

4-[hydroxy(diphenyl)methyl]-1-[2-({[3-(methyloxy)phenyl]methyl}oxy)ethyl]-1-azoniabicyclo[2.2.2]octanebromide

1-Azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (30 mg, 0.102 mmol) wasadded to a solution of1-{[(2-bromoethyl)oxy]methyl}-3-(methyloxy)benzene (35 mg, 0.143 mmol)in 2 CH₃CN/3 CHCl₃ (3 mL). The reaction was heated at 60° C. for 96 h.The reaction was concentrated, and the crude product washed with EtOAc(3×1 mL) and then MeOH (1×1 mL). The product was dried under high vacuumto give the title compound (7.7 mg, 14%). LC/MS ESI R_(T) 1.97 min M⁺458

Example 76 Preparation of1-[2-({[4-(1,1-dimethylethyl)phenyl]methyl}oxy)ethyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octanebromide 2-({[4-(1,1-dimethylethyl)phenyl]methyl}oxy)ethanol

Ethylene glycol (0.084 mL, 1.5 mmol) was added to NaH (38 mg, 1.52 mmol,95% in oil) in THF (3 mL). 1-(Bromomethyl)-4-(1,1-dimethylethyl)benzene(0.28 mL, 1.5 mmol) was added to the reaction, and the residual1-(bromomethyl)-4-(1,1-dimethylethyl)benzene was transferred to thereaction tube with additional THF (1 mL). (Bu)₄NI (55 mg, 0.15 mmol) wasthen added, and the reaction was heated at 60° C. for 18 h and then rtfor 4 h. H₂O (2 mL) and EtOAc (2 mL) were added, and the layers wereseparated via pipette. The aqueous layer was extracted with EtOAc (1×1mL), and the combined organic layers were concentrated. The crudeproduct was purified on a SPE cartridge (5 g silica) eluting with thefollowing 10 mL fractions: 10% EtOAc/hexanes (fractions 1,2), 30%EtOAc/hexanes (fractions 3,4), and 50% EtOAc/hexanes (fractions 5,6) togive the title compound (312 mg, 51%). The product was characterized by¹H NMR (400 MHz) in CDCl₃.

1-{[(2-bromoethyl)oxy]methyl}-4-(1,1-dimethylethyl)benzene

A solution of N-bromosuccinimide (272 mg, 1.53 mmol) in DCM (2.5 mL) wasadded to resin-bound triphenylphosphine (510 mg, 1.53 mEquiv, Fluka) inDCM (2.5 mL), and the reaction was stirred at rt for 10 min. A solutionof 2-({[4-(1,1-dimethylethyl)phenyl]methyl}oxy)ethanol (160 mg, 0.768mmol) in DCM (1.5 mL) was added to the reaction, and the residualalcohol was transferred with additional DCM (1.5 mL). The reaction vialwas capped, wrapped in aluminum foil, and stirred at rt for 20 h. Thereaction was filtered through a SPE cartridge (5 g silica) eluting withthe following 10 mL fractions: DCM (fraction 1), 30% EtOAc/hexanes(fraction 2), and 50% EtOAc/hexanes (fraction 3) to give the titlecompound (25 mg, 12%). The product was characterized by ¹H NMR (400 MHz)in CDCl₃.

1-[2-({[4-(1,1-dimethylethyl)phenyl]methyl}oxy)ethyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octanebromide

1-Azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (30 mg, 0.102 mmol) wasadded to a solution of1-{[(2-bromoethyl)oxy]methyl}-4-(1,1-dimethylethyl)benzene (25 mg, 0.143mmol) in 2:3 CH₃CN/CHCl₃ (3 mL), and the reaction was heated at 60° C.for 96 h. The reaction was concentrated, and the crude product washedwith EtOAc (3×1 mL). The product was dried under high vacuum to give thetitle compound (9 mg, 16%). LC/MS ESI R_(T) 2.28 min M⁺484

Example 77 Preparation of1-(2-{[(4-fluorophenyl)methyl]oxy}ethyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octanebromide 2-{[(4-fluorophenyl)methyl]oxy}ethanol

Ethylene glycol (0.084 mL, 1.5 mmol) was added to NaH (38 mg, 1.52 mmol,95% in oil) in THF (3 mL). 1-(Bromomethyl)-4-fluorobenzene (0.19 mL, 1.5mmol) was added to the reaction, and the residual1-(bromomethyl)-4-fluorobenzene was transferred to the reaction tubewith additional THF (1 mL). (Bu)₄NI (55 mg, 0.15 mmol) was added, andthe reaction was heated at 60° C. for 18 h and then rt for 4 h. H₂O (2mL) and EtOAc (2 mL) were added, and the layers were separated viapipette. The aqueous layer was extracted with EtOAc (1×1 mL), and thecombined organic layers were concentrated. The crude product waspurified on a SPE cartridge (5 g silica) eluting with the following 10mL fractions: 30% EtOAc/hexanes (fractions 1,2), 50% EtOAc/hexanes(fraction 3), and 75% EtOAc/hexanes (fraction 4) to give the titlecompound (122 mg, 48%). The product was characterized by ¹H NMR (400MHz) in CDCl₃.

1-{[(2-bromoethyl)oxy]methyl}-4-fluorobenzene

A solution of N-bromosuccinimide (272 mg, 1.53 mmol) in DCM (2.5 mL) wasadded to resin-bound triphenylphosphine (510 mg, 1.53 mEquiv, Fluka) inDCM (2.5 mL), and the reaction was stirred at rt for 10 min. A solutionof 2-{[(4-fluorophenyl)methyl]oxy}ethanol (122 mg, 0.717 mmol) in DCM(1.5 mL) was added to the reaction, and the residual alcohol wastransferred with additional DCM (1.5 mL). The reaction vial was capped,wrapped in aluminum foil, and stirred at rt for 20 h. The reaction wasfiltered through a SPE cartridge (5 g silica) eluting with the following10 mL fractions: DCM (fraction 1), 30% EtOAc/hexanes (fraction 2), and50% EtOAc/hexanes (fraction 3) to give the title compound (80 mg, 48%).The product was characterized by ¹H NMR (400 MHz) in CDCl₃.

1-(2-{[(4-fluorophenyl)methyl]oxy}ethyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octanebromide

1-Azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (30 mg, 0.102 mmol) wasadded to a solution of 1-{[(2-bromoethyl)oxy]methyl}-4-fluorobenzene (33mg, 0.143 mmol) in 2:3 CH₃CN/CHCl₃ (3 mL), and the reaction was heatedat 60° C. for 96 h. The reaction was concentrated, and the crude productwashed with EtOAc (3×1 mL). The product was dried under high vacuum togive the title compound (9 mg, 16%). LC/MS ESI R_(T) 1.89 min M⁺446

Example 78 Preparation of1-(2-{[(4-chlorophenyl)methyl]oxy}ethyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octanebromide 2-{[(4-chlorophenyl)methyl]oxy}ethanol

Ethylene glycol (0.084 mL, 1.5 mmol) was added to NaH (38 mg, 1.52 mmol,95% in oil) in THF (3 mL). 1-(Bromomethyl)-4-chlorobenzene (310 mg, 1.5mmol) was added to the reaction, and the residual1-(bromomethyl)-4-chlorobenzene was transferred to the reaction tubewith additional THF (1 mL). (Bu)₄NI (55 mg, 0.15 mmol) was then added,and the reaction was heated at 60° C. for 18 h and then rt for 4 h. H₂O(2 mL) and EtOAc (2 mL) were added, and the layers were separated viapipette. The aqueous layer was extracted with EtOAc (1×1 mL), and thecombined organic layers were concentrated. The crude product waspurified on a SPE cartridge (5 g silica) eluting with the following 10mL fractions: 30% EtOAc/hexanes (fractions 1,2), 50% EtOAc/hexanes(fraction 3), and 75% EtOAc/hexanes (fraction 4) to give the titlecompound (129 mg, 46%). The product was characterized by ¹H NMR (400MHz) in CDCl₃.

1-{[(2-bromoethyl)oxy]methyl}-4-chlorobenzene

A solution of N-bromosuccinimide (272 mg, 1.53 mmol) in DCM (2.5 mL) wasadded to resin-bound triphenylphosphine (510 mg, 1.53 mEquiv, Fluka) inDCM (2.5 mL), and the reaction was stirred at rt for 10 min. A solutionof 2-{[(4-chlorophenyl)methyl]oxy}ethanol (129 mg, 0.691 mmol) in DCM(1.5 mL) was added to the reaction, and the residual alcohol wastransferred with additional DCM (1.5 mL). The reaction vial was capped,wrapped in aluminum foil, and stirred at rt for 20 h. The reaction wasfiltered through a SPE cartridge (5 g silica) eluting with the following10 mL fractions: DCM (fraction 1), 30% EtOAc/hexanes (fraction 2), and50% EtOAc/hexanes (fraction 3) to give the title compound (98 mg, 57%).The product was characterized by ¹H NMR (400 MHz) in CDCl₃.

1-(2-{[(4-chlorophenyl)methyl]oxy}ethyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octanebromide

1-Azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (30 mg, 0.102 mmol) wasadded to a solution of 1-{[(2-bromoethyl)oxy]methyl}-4-chlorobenzene (36mg, 0.143 mmol) in 2:3 CH₃CN/CHCl₃ (3 mL), and the reaction was heatedat 60° C. for 96 h. The reaction was concentrated, and the crude productwashed with EtOAc (3×1 mL). The product was dried under high vacuum togive the title compound (17.4 mg, 32%). LC/MS ESI R_(T) 2.09 min M⁺462

Example 79 Preparation of1-(2-{[(4-bromophenyl)methyl]oxy}ethyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octanebromide 2-{[(4-bromophenyl)methyl]oxy}ethanol

Ethylene glycol (0.084 mL, 1.5 mmol) was added to NaH (38 mg, 1.52 mmol,95% in oil) in THF (3 mL). 1-Bromo-4-(bromomethyl)benzene (370 mg, 1.5mmol) was added to the reaction, and the residual1-bromo-4-(bromomethyl)benzene was transferred to the reaction tube withadditional THF (1 mL). (Bu)₄NI (55 mg, 0.15 mmol) was then added, andthe reaction was heated at 60° C. for 18 h and then rt for 4 h. H₂O (2mL) and EtOAc (2 mL) were added, and the layers were separated viapipette. The aqueous layer was extracted with EtOAc (1×1 mL), and thecombined organic layers were concentrated. The crude product waspurified on a SPE cartridge (5 g silica) eluting with the following 10mL fractions: 30% EtOAc/hexanes (fractions 1,2), 50% EtOAc/hexanes(fraction 3), and 75% EtOAc/hexanes (fraction 4) to give the titlecompound (139 mg, 40%). The product was characterized by ¹H NMR (400MHz) in CDCl₃.

1-bromo-4-{[(2-bromoethyl)oxy]methyl}benzene

A solution of N-bromosuccinimide (272 mg, 1.53 mmol) in DCM (2.5 mL) wasadded to resin-bound triphenylphosphine (510 mg, 1.53 mEquiv, Fluka) inDCM (2.5 mL), and the reaction was stirred at rt for 10 min. A solutionof 2-{[(4-bromophenyl)methyl]oxy}ethanol (139 mg, 0.601 mmol) in DCM(1.5 mL) was added to the reaction, and the residual alcohol wastransferred with additional DCM (1.5 mL). The reaction vial was capped,wrapped in aluminum foil, and stirred at rt for 20 h. The reaction wasfiltered through a SPE cartridge (5 g silica) eluting with the following10 mL fractions: DCM (fraction 1), 30% EtOAc/hexanes (fraction 2), and50% EtOAc/hexanes (fraction 3) to give the title compound (87 mg, 49%).The product was characterized by ¹H NMR (400 MHz) in CDCl₃.

1-(2-{[(4-bromophenyl)methyl]oxy}ethyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octanebromide

1-Azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (30 mg, 0.102 mmol) wasadded to a solution of 1-bromo-4-{[(2-bromoethyl)oxy]methyl}benzene (42mg, 0.143 mmol) in 2:3 CH₃CN/CHCl₃ (3 mL), and the reaction was heatedat 60° C. for 96 h. The reaction was concentrated, and the crude productwashed with EtOAc (3×1 mL). The product was dried under high vacuum togive the title compound (19.4 mg, 32%). LC/MS ESI R_(T) 2.07 min M⁺506

Example 80 Preparation of1-(2-{[(4-cyanophenyl)methyl]oxy}ethyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octanebromide 4-{[(2-hydroxyethyl)oxy]methyl}benzonitrile

Ethylene glycol (0.084 mL, 1.5 mmol) was added to NaH (38 mg, 1.52 mmol,95% in oil) in THF (3 mL). 4-(Bromomethyl)benzonitrile (290 mg, 1.5mmol) was added to the reaction, and the residual4-(bromomethyl)benzonitrile was transferred to the reaction tube withadditional THF (1 mL). (Bu)₄NI (55 mg, 0.15 mmol) was then added, andthe reaction was heated at 60° C. for 18 h and then rt for 4 h. H₂O (2mL) and EtOAc (2 mL) were added, and the layers were separated viapipette. The aqueous layer was extracted with EtOAc (1×1 mL), and thecombined organic layers were concentrated. The crude product waspurified on a SPE cartridge (5 g silica) eluting with the following 10mL fractions: 10% EtOAc/hexanes (fractions 1,2), 30% EtOAc/hexanes(fractions 3,4), 50% EtOAc/hexanes (fractions 5-7), and 75%EtOAc/hexanes (fraction 8) to give the title compound (95 mg, 36%). Theproduct was characterized by ¹H NMR (400 MHz) in CDCl₃.

4-{[(2-bromoethyl)oxy]methyl}benzonitrile

A solution of N-bromosuccinimide (272 mg, 1.53 mmol) in DCM (2.5 mL) wasadded to resin-bound triphenylphosphine (510 mg, 1.53 mEquiv, Fluka) inDCM (2.5 mL), and the reaction was stirred at rt for 10 min. A solutionof 4-{[(2-hydroxyethyl)oxy]methyl}benzonitrile (95 mg, 0.536 mmol) inDCM (1.5 mL) was added to the reaction, and the residual alcohol wastransferred with additional DCM (1.5 mL). The reaction vial was capped,wrapped in aluminum foil, and stirred at rt for 20 h. The reaction wasfiltered through a SPE cartridge (5 g silica) eluting with the following10 mL fractions: DCM (fraction 1), 30% EtOAc/hexanes (fraction 2), and50% EtOAc/hexanes (fraction 3) to give the title compound (60 mg, 47%).The product was characterized by ¹H NMR (400 MHz) in CDCl₃.

1-(2-{[(4-cyanophenyl)methyl]oxy}ethyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octanebromide

1-Azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (30 mg, 0.102 mmol) wasadded to a solution of 4-{[(2-bromoethyl)oxy]methyl}benzonitrile (34 mg,0.143 mmol) in 2:3 CH₃CN/CHCl₃ (3 mL), and the reaction was heated at60° C. for 96 h. The reaction was concentrated, and the crude productwashed with EtOAc (3×1 mL). The product was dried under high vacuum togive the title compound (40 mg, 74%). LC/MS ESI R_(T) 1.82 min M⁺453

Example 81 Preparation of4-[hydroxy(diphenyl)methyl]-1-{2-[(2-naphthalenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octanebromide 2-[(2-naphthalenylmethyl)oxy]ethanol

Ethylene glycol (0.084 mL, 1.5 mmol) was added to NaH (38 mg, 1.52 mmol,95% in oil) in THF (3 mL). 2-(Bromomethyl)naphthalene (330 mg, 1.5 mmol)was added to the reaction, and the residual 2-(bromomethyl)naphthalenewas transferred to the reaction tube with additional THF (1 mL). (Bu)₄NI(55 mg, 0.15 mmol) was then added, and the reaction was heated at 60° C.for 18 h and then rt for 4 h. H₂O (2 mL) and EtOAc (2 mL) were added,and the layers were separated via pipette. The aqueous layer wasextracted with EtOAc (1×1 mL), and the combined organic layers wereconcentrated. The crude product was purified on a SPE cartridge (5 gsilica) eluting with the following 10 mL fractions: 30% EtOAc/hexanes(fractions 1,2), 50% EtOAc/hexanes (fraction 3), and 75% EtOAc/hexanes(fraction 4) to give the title compound (101 mg, 33%). The product wascharacterized by ¹H NMR (400 MHz) in CDCl₃.

2-{[(2-bromoethyl)oxy]methyl}naphthalene

A solution of N-bromosuccinimide (272 mg, 1.53 mmol) in DCM (2.5 mL) wasadded to resin-bound triphenylphosphine (510 mg, 1.53 mEquiv, Fluka) inDCM (2.5 mL), and the reaction was stirred at rt for 10 min. A solution2-[(2-naphthalenylmethyl)oxy]ethanol (101 mg, 0.499 mmol) in DCM (1.5mL) was added to the reaction, and the residual alcohol was transferredwith additional DCM (1.5 mL). The reaction vial was capped, wrapped inaluminum foil, and stirred at rt for 20 h. The reaction was filteredthrough a SPE cartridge (5 g silica) eluting with the following 10 mLfractions: DCM (fraction 1), 30% EtOAc/hexanes (fraction 2), and 50%EtOAc/hexanes (fraction 3) to give the title compound (57 mg, 43%). Theproduct was characterized by ¹H NMR (400 MHz) in CDCl₃.

4-[hydroxy(diphenyl)methyl]-1-{2-[(2-naphthalenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octanebromide

1-Azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (30 mg, 0.102 mmol) wasadded to a solution of 2-{[(2-bromoethyl)oxy]methyl}naphthalene (38 mg,0.143 mmol) in 2:3 CH₃CN/CHCl₃ (3 mL), and the reaction was heated at60° C. for 96 h. The reaction was concentrated, and the crude productwashed with EtOAc (3×1 mL). The product was dried under high vacuum togive the title compound (48.1 mg, 84%). LC/MS ESI R_(T) 2.04 min M⁺478

Example 82 Preparation of1-(2-{[(3-fluorophenyl)methyl]oxy}ethyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octanebromide 2-{[(3-fluorophenyl)methyl]oxy}ethanol

Ethylene glycol (0.1 mL, 1.79 mmol) was added to NaH (46 mg, 1.81 mmol,95% in oil) in THF (5 mL). 1-(Bromomethyl)-3-fluorobenzene (0.22 mL,1.79 mmol) was added to the reaction, and the reaction was heated at 60°C. for 5 days. H₂O (2 mL) and EtOAc (2 mL) were added, and the layerswere separated via pipette. The aqueous layer was extracted with EtOAc(3×1 mL), and the combined organic layers were washed with saturatedNaCl (1×2 mL), dried (Na₂SO₄), and concentrated. The crude product waspurified on a SPE cartridge (5 g silica) eluting with the following 10mL fractions: 30% EtOAc/hexanes (fractions 1,2), 50% EtOAc/hexanes(fraction 3), and 75% EtOAc/hexanes (fraction 4) to give the titlecompound (76.2 mg, 25%). The product was characterized by ¹H NMR (400MHz) in CDCl₃.

1-{[(2-bromoethyl)oxy]methyl}-3-fluorobenzene

N-bromosuccinimide (146 mg, 0.820 mmol) was added to resin-boundtriphenylphosphine (274 mg, 0.822 mEquiv, Fluka) and2-{[(3-fluorophenyl)methyl]oxy}ethanol (70 mg, 0.411 mmol) in DCM (4mL). The reaction vial was sealed with a Teflon-lined cap, wrapped inaluminum foil, and shaken at rt for 17 h. The reaction was filteredthrough a SPE cartridge (5 g silica) eluting with the following 10 mLfractions: DCM (fraction 1), 30% EtOAc/hexanes (fraction 2), and 50%EtOAc/hexanes (fraction 3) to give the title compound (75 mg, 78%). Theproduct was characterized by ¹H NMR (400 MHz) in CDCl₃.

1-(2-{[(3-fluorophenyl)methyl]oxy}ethyl)-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octanebromide

1-Azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (94 mg, 0.321 mmol) wasadded to a solution of 1-{[(2-bromoethyl)oxy]methyl}-3-fluorobenzene (75mg, 0.321 mmol) in 2:3 CH₃CN/CHCl₃ (4 mL), and the reaction was heatedat 60° C. for 3 days. The reaction was concentrated under reducedpressure, and the crude product washed with EtOAc (3×2 mL). The productwas dried under high vacuum to give the title compound (50 mg, 30%).LC/MS ESI R_(T) 1.95 min M⁺446

Example 83 Preparation of4-[hydroxy(diphenyl)methyl]-1-{2-[(1-methyl-1-phenylethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octanebromide 2-[(1-methyl-1-phenylethyl)oxy]ethanol

A catalytic amount of either p-toluene sulfonic acid•H₂O or Bio-Rad SCXresin (analytical grade, 5.1 meq/g, AG 50W-X8) was added to□-methylstyrene (0.5 mL, 3.85 mmol) and ethylene glycol (0.21 mL, 3.85mmol), and the reaction was stirred at rt for 5 days. The reactionmixture was loaded directly onto a SPE cartridge (10 g silica) andeluted with the following 10 mL fractions: 10% EtOAc/hexanes (fractions1,2), 30% EtOAc/hexanes (fractions 3,4), and 50% EtOAc/hexanes(fractions 5,6) to give the title compound (30.5 mg, 4%) for bothconditions. The product was characterized by ¹H NMR (400 MHz) in CDCl₃.

{1-[(2-bromoethyl)oxy]-1-methylethyl}benzene

N-bromosuccinimide (119 mg, 0.666 mmol) was added to resin-boundtriphenylphosphine (222 mg, 0.666 mEquiv, Fluka) and2-[(1-methyl-1-phenylethyl)oxy]ethanol (60 mg, 0.333 mmol) in DCM (4mL). The reaction vial was sealed with a Teflon-lined cap, wrapped inaluminum foil, and shaken at rt for 17 h. The reaction was filteredthrough a SPE cartridge (5 g silica) eluting with the following 10 mLfractions: DCM (fraction 1), 30% EtOAc/hexanes (fraction 2), and 50%EtOAc/hexanes (fraction 3) to give the title compound (34 mg, 42%). Theproduct was characterized by ¹H NMR (400 MHz) in CDCl₃.

4-[hydroxy(diphenyl)methyl]-1-{2-[(1-methyl-1-phenylethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octanebromide

1-Azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (41 mg, 0.14 mmol) wasadded to a solution of {1-[(2-bromoethyl)oxy]-1-methylethyl}benzene (34mg, 0.14 mmol) in 2:3 CH₃CN/CHCl₃ (3 mL), and the reaction was heated at60° C. for 3 days. The reaction was concentrated under reduced pressure,and the crude product washed with EtOAc (3×1 mL). The residue was takenup in 2.5 mL of DMSO and purified by preparatory HPLC (without TFA) togive the title compound (18 mg, 24%). LC/MS ESI R_(T) 2.09 min M⁺456

Example 84 Preparation of4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octanebromide

Method A: 1-Azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.020 g, 0.068mmol) was diluted in CHCl₃ (1.8 mL) and dispensed directly into a 1 dramvial containing 2-bromoethyl phenylmethyl ether (0.022 g, 0.102 mmol).CH₃CN (1.2 mL) was added; the vial was fitted with a stirring bar andcapped. The reaction was stirred and heated at 60° C. for 24 h. Thecontents of the vial were transferred (after removal of stirring bar)into a polypropylene tube and concentrated under Nitrogen. The crudeproduct was collected on a polypropylene tube frit. Excess bromide wasremoved by washing the crude product with EtOAc (5×2 mL) and Hexane (5×2mL). The product was then dried under vacuum to give the title compound(0.008 g, 23.8%).

Method B: To a solution of 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol(3.30 g, 11.2 mmol) in 2 CH₃CN/3 CHCl₃ (200 mL) was added 2-bromoethylphenylmethyl ether (2.31 mL, 14.6 mmol). The solution was stirred at 60°C. for 16 h. The reaction was cooled down to room temperature andconcentrated. EtOAc (200 mL) was added to the solid, and the mixture wasallowed to stir for 1 hour then filtered. The resulting solid was takenup in MeOH (125 mL) and heated to 60° C. The solution was filtered hot,and then cooled back to room temperature. The reaction was concentratedto a low volume of MeOH (˜20 mL) and filtered. Water (75 mL) was thenadded and the resulting mixture was heated at 55° C. with brisk stirringfor 40 min. After cooling to room temperature, the solid was filteredoff, washed with water (20 mL) and dried in a vacuum oven at 45° C. for16 hours to give the title compound (2.47 g, 43.3%). EI-MS m/z 428(M⁺)Rt (1.90 min) ¹H NMR (DMSO-d₆) δ 7.56 (d, 4H, J=1.2), 7.28 (m, 11H),5.95 (s, 1H), 4.50 (s, 2H), 3.81 (d, 2H, J=4.0), 3.48 (t, 6H, J=7.2),3.38 (d, 2H, J=4.0), 2.01 (t, 6H, J=7.2); Elemental analysis(C₂₉H₃₄NO₂Br) C, H, N: calculated, 68.50, 6.74, 2.75; found, 68.28,6.68, 2.73.

The following examples in Table 1 were prepared according to theprocedure outlined in Example 84 method A.

TABLE 1

Ex- MS R_(t) ample R1 [M+] (min) 85

384 1.64 86

434 1.97 87

419 1.51 88

468 2.02 89

463 1.77 90

414 1.84 91

468 1.96 92

402 1.68 93

463 1.82 94

452 1.93 95

402 1.55 96

452 1.97 97

418 2.00 98

398 1.72 99

402 1.60 100

402 1.63 101

453 1.92 102

416 1.87 103

409 1.60 104

440 2.07 105

409 1.55 106

420 1.90 107

420 1.78 108

525 1.67 109

429 1.57 110

420 1.64 111

420 1.67

Example 112 Preparation of1-[2-(1-benzofuran-2-yl)-2-oxoethyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octanebromide

1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.022 g, 0.075 mmol) wasdiluted in CHCl₃ (1.8 mL) and dispensed directly into a 1 dram vialcontaining 1-(1-benzofuran-2-yl)-2-bromoethanone (0.027 g, 0.112 mmol).Added CH₃CN (1.2 mL), the vial was fitted with stirring bar and capped.The reaction was stirred and heated at 60° C. for 24 h and thenconcentrated under vacuum to give a white solid. This residue wasdissolved in DMSO and purified by preparatory HPLC (without TFA) to givethe title compound (0.022 g, 57.4%). LC/MS ESI R_(T) 1.98 min, M⁺452

The following examples in Table 2 were prepared according to theprocedure outlined in Example 112.

TABLE 2

Ex- MS R_(t) ample R1 [M+] (min) 113

437 1.96 114

441 1.92 115

525 2.11 116

488 2.31 117

482 2.46 118

510 1.95 119

462 2.03 120

442 1.95 121

429 1.33 122

534 1.92Abbreviations

-   Ar Argon-   DCM Dichloromethane-   DMF Dimethylformamide-   DMSO Dimethylsulfoxide-   EI/ESI Electrospray ionization-   HPLC High pressure liquid chromatography-   LC Liquid chromatography-   LDA Lithium Diisopropyl Amide-   MS Mass spectrometry-   NMR Nuclear magnetic resonance-   R_(t) Retention time-   rt room temperature-   SPE Solid phase extraction-   TEA Triethylamine-   TFA Trifluoroacetic acid-   THF Tetrahydrofuran

BIOLOGICAL EXAMPLES

The inhibitory effects of compounds at the M₃ mAChR of the presentinvention are determined by the following in vitro and in vivofunctional assays:

Analysis of Inhibition of Receptor Activation by Calcium Mobilization:

Stimulation of mAChRs expressed on CHO cells were analyzed by monitoringreceptor-activated calcium mobilization as previously described (H. M.Sarau et al, 1999. Mol. Pharmacol. 56, 657-663). CHO cells stablyexpressing M₃ mAChRs were plated in 96 well black wall/clear bottomplates. After 18 to 24 hours, media was aspirated and replaced with 100μl of load media (EMEM with Earl's salts, 0.1% RIA-grade BSA (Sigma, St.Louis Mo.), and 4 μM Fluo-3-acetoxymethyl ester fluorescent indicatordye (Fluo-3 AM, Molecular Probes, Eugene, Oreg.) and incubated 1 hr at37° C. The dye-containing media was then aspirated, replaced with freshmedia (without Fluo-3 AM), and cells were incubated for 10 minutes at37° C. Cells were then washed 3 times and incubated for 10 minutes at37° C. in 100 μl of assay buffer (0.1% gelatin (Sigma), 120 mM NaCl, 4.6mM KCl, 1 mM KH₂ PO₄, 25 mM NaH CO₃, 1.0 mM CaCl₂, 1.1 mM MgCl₂, 11 mMglucose, 20 mM HEPES (pH 7.4)). 50 μl of compound (1×10⁻¹¹-1×10⁻⁵ Mfinal in the assay) was added and the plates were incubated for 10 min.at 37° C. Plates were then placed into a fluorescent light intensityplate reader (FLIPR, Molecular Probes) where the dye loaded cells wereexposed to excitation light (488 nm) from a 6 watt argon laser. Cellswere activated by adding 50 μl of acetylcholine (0.1-10 nM final),prepared in buffer containing 0.1% BSA, at a rate of 50 μl/sec. Calciummobilization, monitored as change in cytosolic calcium concentration,was measured as change in 566 nm emission intensity. The change inemission intensity is directly related to cytosolic calcium levels. Theemitted fluorescence from all 96 wells is measured simultaneously usinga cooled CCD camera. Data points are collected every second. This datawas then plotting and analyzed using GraphPad PRISM software.

Methacholine-induced Bronchoconstriction—Potency and Duration of Action

Airway responsiveness to methacholine was determined in awake,unrestrained Balb C mice (n=6 each group). Barometric plethysmographywas used to measure enhanced pause (Penh), a unitless measure that hasbeen shown to correlate with the changes in airway resistance that occurduring bronchial challenge with methacholine(2). Mice were pre-treatedwith 50 μl of compound (0.003-10 μg/mouse) in 50 μl of vehicle (10%DMSO) intranasally (i.n.) and were then placed in the plethysmographychamber a given amount of time following drug administration (15 min—96h). For potency determination, a dose response to a given drug wasperformed, and all measurements were taken 15 min following i.n. drugadministration. For duration of action determination, measurements weretaken anywhere from 15 min to 96 hours following i.n. drugadministration.

Once in the chamber, the mice were allowed to equilibrate for 10 minbefore taking a baseline Penh measurement for 5 minutes. Mice were thenchallenged with an aerosol of methacholine (10 mg/ml) for 2 minutes.Penh was recorded continuously for 7 min starting at the inception ofthe methacholine aerosol, and continuing for 5 minutes afterward. Datafor each mouse were analyzed and plotted by using GraphPad PRISMsoftware. This experiment allows the determination of duration ofactivity of the administered compound.

The present compounds are useful for treating a variety of indications,including but not limited to respiratory-tract disorders such as chronicobstructive lung disease, chronic bronchitis, asthma, chronicrespiratory obstruction, pulmonary fibrosis, pulmonary emphysema, andallergic rhinitis.

Muscarinic Receptor Radioligand Binding Assays

Radioligand binding studies using 0.5 nM [³H]-N-methyl scopolamine (NMS)in a SPA format is used to assess binding of muscarinic antagonists toM₁, M₂, M₃, M₄ and M₅ muscarinic acetylcholine receptors. In a 96-wellplate, the SPA beads are pre-incubated with receptor-containing membranefor 30 min at 4° C. Then 50 mM HEPES and the test compound are added andincubated at room temperature (shaking) for 2 hours. The beads are thenspun down and counted using a scintillation counter.

Evaluation of Potency and Duration of Action in Isolated Guinea PigTrachea

Tracheae were removed from adult male Hartely guinea pigs (CharlesRiver, Raleigh, N.C.; 400-600 grams) and placed into modifiedKrebs-Henseleit solution. Composition of the solution was (mM): NaCl113.0, KCl 4.8, CaCl₂ 2.5, KH₂PO₄ 1.2, MgSO₄ 1.2, NaHCO₃ 25.0 anddextrose 11.0. which was gassed with 95% O₂: 5% CO₂ and maintained at37° C. Each trachea was cleaned of adherent tissue and openedlengthwise. Epithelium was removed by gently rubbing the luminal surfacewith a cotton-tipped applicator. Individual strips were cut,approximately 2 cartilage rings in width, and suspended via silk suturein 10-ml water-jacketed organ baths containing Krebs-Henseleit solutionand connected to Grass FT03C force-displacement transducers. Mechanicalresponses were recorded isometrically by MP100WS/Acknowledge dataacquisition system (BIOPAC Systems, Goleta, Calif., www.biopac.com) runon Apple G4 computers. The tissues were equilibrated under a restingtension of 1.5 g, determined to be optimal by length-tension evaluation,and washed with Krebs-Henseleit solution every 15 minutes for one hour.After the equilibration period pulmonary tissues were contracted with 10uM carbachol until reaching plateau, which served as a referencecontraction for data analysis. Tissues were then rinsed every 15 minutesover 1 hour until reaching baseline tone. The preparations were thenleft for at least 30 minutes before the start of the experiment.

Concentration-response curves were obtained by a cumulative addition ofcarbachol in half-log increments (Van Rossum, 1963, Arch. Int.Pharmacodyn., 143:299), initiated at 1 nM. Each concentration was leftin contact with the preparation until the response plateaued before theaddition of the subsequent carbachol concentration. Paired tissues wereexposed to mAChR antagonist compounds or vehicle for 30 min beforecarbachol cumulative concentration-response curves were generated. Alldata is given as mean±standard error of the mean (s.e.m.) with n beingthe number of different animals.

For superfusion (duration of action) studies, the tissues werecontinuously superfused with Krebs-Henseleit solution at 2 ml/min forthe duration of the experiment. Stock solutions of agonist andantagonist were infused (0.02 ml/min) via 22-gauge needle inserted intothe superfusion tubing. Mechanical responses were recorded isometricallyusing a commercially-available data acquisition system(MP100WS/Acknowledge; BIOPAC Systems, Goleta, Calif., www.biopac.com)interfaced with a Macintosh G4 computer (Apple, Cupertino, Calif.www.apple.com). The tissues were suspended under an optimal restingtension of 1.5 g. After a 60 min equilibration period, the tissues werecontracted with carbachol (1 uM) for the duration of the experiment.Upon reaching a sustained contraction isoproterenol (10 uM) wasadministered to maximally relax the tissue, and this change served as areference. Isoproterenol exposure was halted and the carbachol-inducedtension allowed to recover. Muscarinic receptor antagonists infused at asingle concentration per tissue until a sustained level of inhibitionwas attained. The compound was then removed and, once again, thecarbachol-induced tension was allowed to recover.

The following parameters were determined for each concentration ofantagonist, and expressed as the mean±S.E.M. for n individual animals.Inhibition of the carbachol-induced contraction was expressed as apercent of the reference response (isoproterenol) and the time requiredto reach one-half of this relaxation was measured (onset of response).The tension recovery following removal of the compound was determined aswas the time required to reach one-half of the maximum tension recovery(offset of response). At 60 and 180 minutes after removal of theantagonist the remaining level of inhibition was determined andexpressed as a percent of the isoproterenol reference.

Antagonist concentration-response curves were obtained by plotting themaximal relaxation data at 0, 60 and 180-min following antagonistwithdrawal. Recovery, termed shift, was calculated from the ratio of the0-min inhibition curve IC₅₀ and the concentration of compound yielding asimilar tension recovery at 60 and 180 minutes.

Halftimes for onset and offset of response were plotted vs.corresponding concentration and the data were fit with non-linearregression. These values were extrapolated at the IC₅₀ (determined fromthe inhibition concentration-response curve) and designated Ot₅₀ (timerequired, at the IC₅₀ concentration, to reach half of the onsetresponse) and Rt50 (time required, at the IC₅₀ concentration, to reachhalf of the recovery response).

Formulation-Administration

Accordingly, the present invention further provides a pharmaceuticalformulation comprising a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate, or physiologically functional derivative(e.g., salts and esters) thereof, and a pharmaceutically acceptablecarrier or excipient, and optionally one or more other therapeuticingredients.

Hereinafter, the term “active ingredient” means a compound of formula(I), or a pharmaceutically acceptable salt, solvate, or physiologicallyfunctional derivative thereof.

Compounds of formula (I) will be administered via inhalation via themouth or nose.

Dry powder compositions for topical delivery to the lung by inhalationmay, for example, be presented in capsules and cartridges of for examplegelatine, or blisters of for example laminated aluminium foil, for usein an inhaler or insufflator. Powder blend formulations generallycontain a powder mix for inhalation of the compound of the invention anda suitable powder base (carrier/diluent/excipient substance) such asmono-, di- or poly-saccharides (e.g., lactose or starch), organic orinorganic salts (e.g., calcium chloride, calcium phosphate or sodiumchloride), polyalcohols (e.g., mannitol), or mixtures thereof,alternatively with one or more additional materials, such additivesincluded in the blend formulation to improve chemical and/or physicalstability or performance of the formulation, as discussed below, ormixtures thereof. Use of lactose is preferred. Each capsule or cartridgemay generally contain between 20 μg-10 mg of the compound of formula (I)optionally in combination with another therapeutically activeingredient. Alternatively, the compound of the invention may bepresented without excipients, or may be formed into particles comprisingthe compound, optionally other therapeutically active materials, andexcipient materials, such as by co-precipitation or coating.

Suitably, the medicament dispenser is of a type selected from the groupconsisting of a reservoir dry powder inhaler (RDPI), a multi-dose drypowder inhaler (MDPI), and a metered dose inhaler (MDI).

By reservoir dry powder inhaler (RDPI) it is meant as an inhaler havinga reservoir form pack suitable for comprising multiple (un-metereddoses) of medicament in dry powder form and including means for meteringmedicament dose from the reservoir to a delivery position. The meteringmeans may for example comprise a metering cup or perforated plate, whichis movable from a first position where the cup may be filled withmedicament from the reservoir to a second position where the meteredmedicament dose is made available to the patient for inhalation.

By multi-dose dry powder inhaler (MDPI) is meant an inhaler suitable fordispensing medicament in dry powder form, wherein the medicament iscomprised within a multi-dose pack containing (or otherwise carrying)multiple, define doses (or parts thereof) of medicament. In a preferredaspect, the carrier has a blister pack form, but it could also, forexample, comprise a capsule-based pack form or a carrier onto whichmedicament has been applied by any suitable process including printing,painting and vacuum occlusion.

The formulation can be pre-metered (eg as in Diskus, see GB 2242134 orDiskhaler, see GB 2178965, 2129691 and 2169265) or metered in use (eg asin Turbuhaler, see EP 69715). An example of a unit-dose device isRotahaler (see GB 2064336). The Diskus inhalation device comprises anelongate strip formed from a base sheet having a plurality of recessesspaced along its length and a lid sheet hermetically but peelably sealedthereto to define a plurality of containers, each container havingtherein an inhalable formulation containing a compound of formula (I)preferably combined with lactose. Preferably, the strip is sufficientlyflexible to be wound into a roll. The lid sheet and base sheet willpreferably have leading end portions which are not sealed to one anotherand at least one of the said leading end portions is constructed to beattached to a winding means. Also, preferably the hermetic seal betweenthe base and lid sheets extends over their whole width. The lid sheetmay preferably be peeled from the base sheet in a longitudinal directionfrom a first end of the said base sheet.

In one aspect, the multi-dose pack is a blister pack comprising multipleblisters for containment of medicament in dry powder form. The blistersare typically arranged in regular fashion for ease of release ofmedicament therefrom.

In one aspect, the multi-dose blister pack comprises plural blistersarranged in generally circular fashion on a disk-form blister pack. Inanother aspect, the multi-dose blister pack is elongate in form, forexample comprising a strip or a tape.

Preferably, the multi-dose blister pack is defined between two memberspeelably secured to one another. U.S. Pat. Nos. 5,860,419, 5,873,360 and5,590,645 describe medicament packs of this general type. In thisaspect, the device is usually provided with an opening stationcomprising peeling means for peeling the members apart to access eachmedicament dose. Suitably, the device is adapted for use where thepeelable members are elongate sheets which define a plurality ofmedicament containers spaced along the length thereof, the device beingprovided with indexing means for indexing each container in turn. Morepreferably, the device is adapted for use where one of the sheets is abase sheet having a plurality of pockets therein, and the other of thesheets is a lid sheet, each pocket and the adjacent part of the lidsheet defining a respective one of the containers, the device comprisingdriving means for pulling the lid sheet and base sheet apart at theopening station.

By metered dose inhaler (MDI) it is meant a medicament dispensersuitable for dispensing medicament in aerosol form, wherein themedicament is comprised in an aerosol container suitable for containinga propellant-based aerosol medicament formulation. The aerosol containeris typically provided with a metering valve, for example a slide valve,for release of the aerosol form medicament formulation to the patient.The aerosol container is generally designed to deliver a predetermineddose of medicament upon each actuation by means of the valve, which canbe opened either by depressing the valve while the container is heldstationary or by depressing the container while the valve is heldstationary.

Spray compositions for topical delivery to the lung by inhalation mayfor example be formulated as aqueous solutions or suspensions or asaerosols delivered from pressurised packs, such as a metered doseinhaler, with the use of a suitable liquefied propellant. Aerosolcompositions suitable for inhalation can be either a suspension or asolution and generally contain the compound of formula (I) optionally incombination with another therapeutically active ingredient and asuitable propellant such as a fluorocarbon or hydrogen-containingchlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes,e.g. dichlorodifluoromethane, trichlorofluoromethane,dichlorotetra-fluoroethane, especially 1,1,1,2-tetrafluoroethane,1,1,1,2,3,3,3-heptafluoro-n-propane or a mixture thereof. Carbon dioxideor other suitable gas may also be used as propellant. The aerosolcomposition may be excipient free or may optionally contain additionalformulation excipients well known in the art such as surfactants egoleic acid or lecithin and cosolvents eg ethanol. Pressurisedformulations will generally be retained in a canister (eg an aluminiumcanister) closed with a valve (eg a metering valve) and fitted into anactuator provided with a mouthpiece.

Medicaments for administration by inhalation desirably have a controlledparticle size. The optimum aerodynamic particle size for inhalation intothe bronchial system for localized delivery to the lung is usually 1-10μm, preferably 2-5 μm. The optimum aerodynamic particle size forinhalation into the alveolar region for achieving systemic delivery tothe lung is approximately 0.5-3 μm, preferably 1-3 μm. Particles havingan aerodynamic size above 20 μm are generally too large when inhaled toreach the small airways. Average aerodynamic particle size of aformulation may measured by, for example cascade impaction. Averagegeometric particle size may be measured, for example by laserdiffraction, optical means.

To achieve a desired particle size, the particles of the activeingredient as produced may be size reduced by conventional means eg bycontrolled crystallization, micronisation or nanomilling. The desiredfraction may be separated out by air classification. Alternatively,particles of the desired size may be directly produced, for example byspray drying, controlling the spray drying parameters to generateparticles of the desired size range. Preferably, the particles will becrystalline, although amorphous material may also be employed wheredesirable. When an excipient such as lactose is employed, generally, theparticle size of the excipient will be much greater than the inhaledmedicament within the present invention, such that the “coarse” carrieris non-respirable. When the excipient is lactose it will typically bepresent as milled lactose, wherein not more than 85% of lactoseparticles will have a MMD of 60-90 μm and not less than 15% will have aMMD of less than 15 μm. Additive materials in a dry powder blend inaddition to the carrier may be either respirable, i.e., aerodynamicallyless than 10 microns, or non-respirable, i.e., aerodynamically greaterthan 10 microns.

Suitable additive materials which may be employed include amino acids,such as leucine; water soluble or water insoluble, natural or syntheticsurfactants, such as lecithin (e.g., soya lecithin) and solid statefatty acids (e.g., lauric, palmitic, and stearic acids) and derivativesthereof (such as salts and esters); phosphatidylcholines; sugar esters.Additive materials may also include colorants, taste masking agents(e.g., saccharine), anti-static-agents, lubricants (see, for example,Published PCT Patent Appl. No. WO 87/905213, the teachings of which areincorporated by reference herein), chemical stabilizers, buffers,preservatives, absorption enhancers, and other materials known to thoseof ordinary skill.

Sustained release coating materials (e.g., stearic acid or polymers,e.g. polyvinyl pyrolidone, polylactic acid) may also be employed onactive material or active material containing particles (see, forexample, Patent Nos. U.S. Pat. No. 3,634,582, GB 1,230,087, GB1,381,872, the teachings of which are incorporated by reference herein).

Intranasal sprays may be formulated with aqueous or non-aqueous vehicleswith the addition of agents such as thickening agents, buffer salts oracid or alkali to adjust the pH, isotonicity adjusting agents oranti-oxidants.

Solutions for inhalation by nebulation may be formulated with an aqueousvehicle with the addition of agents such as acid or alkali, buffersalts, isotonicity adjusting agents or antimicrobials. They may besterilised by filtration or heating in an autoclave, or presented as anon-sterile product.

Preferred unit dosage formulations are those containing an effectivedose, as herein before recited, or an appropriate fraction thereof, ofthe active ingredient.

Throughout the specification and the claims which follow, unless thecontext requires otherwise, the word ‘comprise’, and variations such as‘comprises’ and ‘comprising’, will be understood to imply the inclusionof a stated integer or step or group of integers but not to theexclusion of any other integer or step or group of integers or steps.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The above description fully discloses the invention including preferredembodiments thereof. Modifications and improvements of the embodimentsspecifically disclosed herein are within the scope of the followingclaims. Without further elaboration, it is believed that one skilled inthe art can, using the preceding description, utilize the presentinvention to its fullest extent. Therefore the Examples herein are to beconstrued as merely illustrative and not a limitation of the scope ofthe present invention in any way. The embodiments of the invention inwhich an exclusive property or privilege is claimed are defined asfollows.

1. The compound which is4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octanebromide.
 2. A pharmaceutical composition comprising4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octanebromide and a pharmaceutically acceptable carrier thereof.
 3. Thecompound

wherein X is a pharmaceutically acceptable anion.
 4. The compoundaccording to claim 3 wherein the pharmaceutically acceptable anion ischloride, bromide, iodide, hydroxide, sulfate, nitrate, phosphate,acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate,succinate, mandelate, methanesulfonate or p-toluenesulfonate.
 5. Thecompound according to claim 3 wherein the pharmaceutically acceptableanion is bromide.
 6. The compound according to claim 3 wherein thepharmaceutically acceptable anion is iodide.
 7. A pharmaceuticalcomposition comprising the compound

wherein X is a pharmaceutically acceptable anion, and a pharmaceuticallyacceptable carrier thereof.
 8. The composition according to claim 7wherein the pharmaceutically acceptable anion is chloride, bromide,iodide, hydroxide, sulfate, nitrate, phosphate, acetate,trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate,mandelate, methanesulfonate or p-toluenesulfonate.
 9. The compositionaccording to claim 7 wherein the pharmaceutically acceptable anion isbromide.
 10. The composition according to claim 7 wherein thepharmaceutically acceptable anion is iodide.
 11. A pharmaceuticalcomposition according to claim 2 in a form suitable for administrationby oral or nasal inhalation.
 12. A pharmaceutical composition accordingto claim 11 wherein the form is suitable for administration byinhalation via a medicament dispenser selected from a reservoir drypowder inhaler, multi-dose dry powder inhaler, or a metered doseinhaler.
 13. A pharmaceutical composition according to claim 2 which isa dry powder composition.
 14. A pharmaceutical composition according toclaim 2 wherein the pharmaceutically acceptable carrier is lactose. 15.A pharmaceutical composition according to claim 7 in a form suitable foradministration by oral or nasal inhalation.
 16. A pharmaceuticalcomposition according to claim 15 wherein the form is suitable foradministration by inhalation via a medicament dispenser selected from areservoir dry powder inhaler, a multi-dose dry powder inhaler, or ametered dose inhaler.
 17. A pharmaceutical composition according toclaim 7 which is a dry powder composition.
 18. A pharmaceuticalcomposition according to claim 7 wherein the pharmaceutically acceptablecarrier is lactose.